Re: 신경-면역 교신.. 암치료 기전과 치료적 의미 2025 네이처!!

[문형철]

본인이 암을 앓고 있거나

가족이 암에 걸려 고통을 받고 있다면 

이 논문을 기반으로 큰 틀의 치료방향을 세울 수 있을 듯!!

실천적 지혜 - 연락바랍니다 01046552968

이유) 한의사가 가진 침, 전침, 부항, 수기치료로 거의 모든 신경을 자극할 수 있다!!

         이 논문은 자극을 주면 왜 어떻게 암세포 미세환경이 바뀌어 면역세포가 암세포를 제거하는가라는 이야기다

위 논리를 정확하게 이해하고

암치료를 위해 체크해야 할일

   1) 면역세포를 정상화하는 신경자극을 주는 다양한 방법은 무엇인가?

   2) 어디에 자극할 것인가?  

   3) 어떻게 자극할 것인가?

   4) 언제(자극 시간, carcadian rhythm) 자극할 것인가?  

1. nature  
2. signal transduction and targeted therapy  
3. review articles  
4. article

• Review Article
• Open access
• Published: 02 June 2025

Neuro-immune crosstalk in cancer: mechanisms and therapeutic implications

• Tianyi Pu, 
• Jiazheng Sun, 
• Guosheng Ren & 
• Hongzhong Li 

Signal Transduction and Targeted Therapy volume 10, Article number: 176 (2025) Cite this article

• 14k Accesses

• 11 Citations

• 15 Altmetric

• Metricsdetails

Abstract

The nervous system precisely regulates physiological activities throughout the body, controlling not only muscle movement, sensory perception, cognition, and responses to external stimuli but also the immune system. In the tumor microenvironment (TME), neural components are important constituents that control the genesis, invasion, and metastasis of tumors by regulating the immune system. The nervous system modulates the tumor immune microenvironment (TIME) through localized control mechanisms (such as sensory, sympathetic, and parasympathetic innervation, as well as glial cell regulation) or via systemic adjustments, including circadian rhythm entrainment, stress modulation, and gut-brain axis regulation. To ensure their survival and proliferation, tumor cells can mimic the anti-inflammatory profiles of neuronal cells by expressing corresponding molecules to evade immune surveillance. Owing to these molecular similarities, the immune system’s targeted attack on the nervous system can lead to neurological damage, exacerbate patient conditions, and elevate mortality rates. Therefore, a detailed understanding of how the nervous and immune systems coordinate and regulate the TME can provide new perspectives and methods for the prevention and treatment of cancer. In this review, we focus on recent studies exploring the bidirectional interplay between the nervous system and tumors mediated by the immune system: how neural activity modulates tumor immunity, and conversely, how tumor-driven immune changes impact nervous system function.

초록

신경계는

근육 운동, 감각 지각, 인지, 외부 자극에 대한 반응뿐만 아니라

면역계까지 통제하며 전신에 걸친 생리적 활동을 정밀하게 조절한다.

종양 미세환경(TME)에서

신경 구성 요소는

면역계를 조절함으로써 종양의 발생, 침습 및 전이를 제어하는 중요한 구성 요소이다.

신경계는

국소적 조절 기전(감각, 교감 및 부교감 신경 분포, 신경교 세포 조절 등)이나

일주기 리듬 동기화,

스트레스 조절,

장-뇌 축 조절을 포함한 전신적 조정을 통해 종양 면역 미세환경(TIME)을 조절한다.

The nervous system modulates the tumor immune microenvironment (TIME)

through localized control mechanisms

(such as sensory, sympathetic, and parasympathetic innervation, as well as glial cell regulation) or

via systemic adjustments,

including circadian rhythm entrainment, stress modulation, and gut-brain axis regulation

신경계와 circadian rhythm이 면역 및 종양 미세환경을 조절하는 기본 분자기전은 다음 세 가지 핵심 축으로 정리할 수 있습니다:​

1. 핵심 Circadian Clock 유전자 (CLOCK, BMAL1, PER, CRY)의 역할
**시상하부(SCN)**에 위치한 중심 시계는 CLOCK-BMAL1 이합체를 통해 주기적인 유전자 발현을 조절하며, 이는 말초 조직과 면역세포에서도 자율적으로 반복됩니다.​

CLOCK, BMAL1 등의 core clock 유전자는 E-box 부위에 결합해 주기적으로 다양한 신호전달 유전자(예: 세포주기 조절, 대사 경로, 면역유전자)의 발현을 조절합니다.​

PER, CRY 단백질은 음성 피드백 루프를 돌며 CLOCK/BMAL1 활성을 억제하여 24시간 주기의 oscillation을 만들고, 이로써 세포 내 다양한 대사/신호 pathway 리듬을 부여합니다.​

2. 신경–면역 교차조절(Neuroimmune Crosstalk) 분자기전
SCN에서 생성된 신경-호르몬 신호(멜라토닌, 코르티솔 등)는 말초 조직의 면역세포 리듬을 조율하고, 각 면역세포(마크로파지, T세포, NK 세포)는 자율적인 clock 유전자를 통해 시간대별 활성에 차이가 생깁니다.​

BMAL1은 Polycomb Repressor Complex 2(PRC2)와 상호작용해 마크로파지 및 단구에서 CCL2·CCL8·S100a8 등 chemokine 유전자 발현을 억제하여 리듬성 면역세포 이동을 조절합니다.​

REV-ERBα는 인플라메이션 조절과 연동되어 IL-6·CCL2 유전자 발현을 억제하는 역할을 하며, 시간에 따른 염증 유전자 억제 타이밍에 기여합니다.​

3. 암 미세환경에서 circadian clock과 신호경로 연계
종양 세포와 미세환경의 CLOCK/BMAL1 발현 저하는 종양 성장, 면역회피, 암 줄기세포 특성(Stemness) 강화, 그리고 angiogenesis를 촉진하는 방향으로 작용합니다.​

다양한 암 환경에서 NF-κB 신호, 세포주기, RTK 경로, 대사 회로가 circadian 유전자 변이 또는 발현 저하와 독립적으로 교차되며, 특히 NF-κB와 CRY/BMAL1의 상호작용은 암세포 항원 제시, 면역관문유전자(PD-L1 등) 조절에도 영향을 미칩니다.​

종양 미세환경에서는 CD8+ T세포, FoxP3+ Treg, M1/M2 마크로파지 비율이 circadian 리듬에 따라 변하는데, circadian disruption시 M1/M2 균형이 붕괴되고, 면역억제 미세환경이 형성되어 암 면역회피가 심화됩니다.​

참고 논문
Ding J et al., "Circadian rhythm regulation in the immune system"​

J Li et al., "Circadian Rhythms in Tumor Regulation"​

Lin Y et al., "The role of circadian clock in regulating cell functions"​

Yang Y et al., "Circadian clock associates with tumor microenvironment in lung cancer"​

Pick R et al., "Circadian Rhythms in Anticancer Immunity: Mechanisms"​

병렬적인 분자기전의 핵심은 SCN-시계 유전자(중추), 면역세포 시계유전자(말초), 그리고 이들의 신호 연결·상호조절입니다. 이 과정이 깨질 때는 암 미세환경이 면역억제성으로 변화하여 치료 저항성이 심화됩니다.

https://www.nature.com/articles/s41392-022-00899-y

신경계 및 circadian rhythm 분자기전의 최신 연구에 기반해, 임상적으로 음식, 전기치료, 침치료, 수기치료, 발효대사산물을 조합해 암치료에 활용할 수 있는 전략들을 다음과 같이 정리할 수 있습니다:​

음식 및 식이요법: chrono-nutrition & 미생물대사 조절
음식 섭취 시간과 식이 구성(식이섬유, 다중불포화지방산 등)은 circadian clock 및 gut microbiota에 직접적 영향.​

**특정 시간대(예: 낮 또는 밤)에 음식 섭취를 최적화(chrononutrition)**하면 암 미세환경 내 면역세포 인필과 염증 분비가 유리하게 조절됨.​

발효대사산물(SCFAs, 프로바이오틱스 대사산물)은 면역억제성 TME를 개선, T세포 및 마크로파지 활성 증가, tumor-associated macrophage 균형을 복원.​

전기치료 및 침치료: circadian clock 동기화 및 면역조절
**미세전류자극(Microcurrent stimulation, MCS)**은 마크로파지와 면역세포의 circadian gene(CLOCK, BMAL1 등) 발현 및 활성 조절.​

MCS는 암 미세환경 내 항암성 마크로파지(M1) 활성, 면역관문유전자(PD-L1) 발현 조절로 면역치료 효과 증대.​

침치료와 electroacupuncture는 시상하부 SCN과 말초 면역세포 clock gene 동기화를 촉진하여 염증 조절, 사이토카인 균형, 암 진행 억제.​

수기치료(마사지, 운동): 조직 재생 및 면역세포 리듬 조절
수기치료 및 물리치료는 시계유전자(BMAL1 등) 동기화를 유도, fibroblast 세포 활성 및 조직 재생력 강화.​

낮 시간대(생체리듬이 활성화되는 시간)에 재활 또는 수기치료를 시행할 경우 면역세포 인필, 조직복원력, 항암미세환경 조성이 더 효과적임.​

운동(특히 인터벌 트레이닝)은 circadian 리듬과 면역세포 활성 증진에 긍정적 효과, 암성 피로 및 염증 개선.​

발효대사산물 및 장내미생물 조절: rhythms-microbiota-microenvironment axis
장내미생물–시계유전자–미세환경 축(rhythms-microbiota-microenvironment axis)이 최근 주요 타깃.​

발효대사산물(예: butyrate, propionate)은 장내 면역세포의 clock gene 발현 조절, 면역관문억제세포(골수유래억제세포, MDSC) 감소, 항종양 CD8+ T세포 증가에 기여.​

비율 불균형 및 clock gene dysregulation이 암 진행 및 치료 저항성 원인, 시간대별 식이/프로바이오틱스/SCFA 투여가 개선책으로 연구 중.​

임상적 적용: Chronotherapy와 통합치료 전략
**항암치료(화학, 면역, 방사선 등)를 circadian 리듬에 맞춰 시행(chronotherapy)**할 경우, 암세포 대사, 면역반응, 부작용 빈도 등 주요 효능 지표가 현저히 개선됨.​

전기치료·침치료와 식이요법, 장내미생물 조절을 병합하는 통합치료가 immunosuppressive TME 극복에 효과적임.​

실제 임상에서는 투여시간 최적화(약물, 치료법 등), 미생물대사산물 보충, circadian gene 타깃 biostimulation이 환자 회복 및 치료 반응률을 높임.​

주요 최신 논문
Circadian rhythm disruption and glycolysis reprogramming in tumor microenvironment​

Dysfunctional circadian-driven gut microbiota dynamics in cancer​

Circadian clock modulation by electrotherapy: Macrophage targeting​

Current clinical chronotherapy in oncology​

Chrononutrition and gut-fermentation axis in TME modulation​

Electroacupuncture and circadian clock gene activation​

Temporal synchronization in immunotherapy efficacy​

최신 및 영향력 높은 학술 논문에 따르면, gut–brain axis 조절을 통해 time(종양 면역 미세환경, TME)의 리듬성을 재구축하고 암세포 사멸을 유도하는 대표적 기전은 다음과 같이 정리됩니다:​

핵심 분자·세포 기전
장내미생물–대사산물–뇌–면역 네트워크

장내미생물(gut microbiota)은 단쇄지방산(SCFA, 부티레이트·프로피오네이트 등), 인돌 등의 대사산물을 생산하며, vagus nerve·호르몬(멜라토닌, 세로토닌 등)·면역 신경 신호로 뇌와 양방향 소통을 합니다.​

이 대사산물은 뇌혈관장벽(BBB)·시상하부 SCN·microglia 등 중추신경계 세포의 시계유전자 활성, 염증 및 항암면역 타이밍을 조절합니다.​

장내 환경이 건강할 때 T세포(특히 CD8+, γδ T세포), NK세포, dendritic cell의 circadian 리듬성이 유지·동기화되고, 이로써 종양 microenvironment의 면역반응·암세포 사멸이 극대화됩니다.​

시간의 동기화: TME 내 항암면역 활성의 리듬성

gut–brain axis에 의해 time-dependent manner로 사이토카인, 면역관문(예: PD-1/PD-L1), 마크로파지 극성(M1/M2)이 변화하고, 암세포의 항원성 및 apoptosis 유도 프로세스가 circadian하게 조절.​

landmark 논문(예: Science Advances, Nature, Nat Commun 등)에서는 circadian disruption(수면장애, 교대근무, 식이시간대 변화 등)이 면역세포 리듬을 붕괴시켜 면역억제성 암미세환경(TIME) 및 종양 진행·내성을 악화한다는 점을 대동물·인간 코호트에서 입증.​

SCFA 및 tryptophan 대사 조절, 장내미생물 다양성 증진, 식이리듬 관리를 통해 TIME의 리듬성을 복구시키면 CD8+ T세포, NK세포의 타이밍 맞춤 항암 활성, 종양 apoptosis, 면역관문억제제 반응률 증대 등 임상적 이득이 나타남.​

암세포 사멸 직접 기전

Tryprophan–Kynurenine–AHR 경로: 장내미생물 변형 등으로 tryptophan 대사가 강해지면 IDO1, TDO 효소가 활성화되고, kynurenine-Kyn-AHR 신호가 Treg 유도, DC 기능 저해, CD8+ T세포 활성을 억제해 면역회피 기전 유발.​

Arginine–microglia 재편: arginine 대사의 변화로 M2→M1 microglia 극성이 유도되면, CD8+ T세포 활성화 및 강력한 항암면역 작용이 나타남.​

SCFA 경로: 부티레이트·프로피오네이트는 microglia·T세포 내 BMAL1, PER2 등의 clock gene 발현 및 항염·항암 유전자 발현을 조절, 종양세포 apoptosis 유발 및 TIME 재프로그래밍.​

치료적 응용

landmark 논문들은 microbe-based intervention(예: probiotics, synbiotics, fecal microbiota transplant) 및 식이·생활 리듬관리, 장내미생물 대사산물 타깃화가 종양내 TIME 동기화를 통한 항암효과 증대에 임상적으로 유의함을 입증.​

영향력지수 높은 대표 논문
Wangting Xu et al., "Gut–Brain–Microbiome Axis in the Regulation of Cancer Immunotherapy and Tumor Microenvironment", Frontiers in Immunology, 2025.​

W Lei et al., "Gut microbiota shapes cancer immunotherapy responses", Nature Microbiology, 2025.​

C Munteanu et al., "The Relationship between Circadian Rhythm and Cancer Progression", Cancers, 2024.​

I Aiello et al., "Circadian disruption promotes tumor-immune microenvironment remodeling", Science Advances, 2020.​

Y Lee et al., "Roles of circadian clocks in cancer pathogenesis and therapeutics", Experimental & Molecular Medicine, 2021.​

미주신경 자극치료 (Vagus Nerve Stimulation, VNS)과 암 종양 면역 미세환경(TME) 조절의 기전
최근 공인된 연구들에 따르면, 교감신경 과흥분에 의한 염증 악화와 부교감신경 탈진에 의한 염증 제어 약화 기전인 "inflammatory reflex"에서 중추 역할을 하는 미주신경 자극치료(VNS)는 암 치료에 중요한 적용 가능성을 지니고 있습니다.

염증성 반응 조절과 항염증 신호 강화

VNS는 미주신경을 통해 알파7 니코틴성 아세틸콜린 수용체(α7nAChR)를 활성화하여, 대식세포와 같은 면역세포에서 IL-6, TNF-α, IL-1β 같은 주요 전염증성 사이토카인들의 분비를 억제합니다.

이로 인해 전신 염증과 종양 주변 염증 억제가 가능해져, 종양 미세환경이 면역억제 상태에서 면역자극 상태로 전환됩니다.

종양 미세환경 내 면역세포 활성화 및 재프로그래밍

VNS는 CD8+ T 세포 및 자연살해세포(NK cell)의 활성도를 증가시켜 직접적인 암세포 사멸을 촉진합니다.

또한 면역관문억제제(ICI) 치료 효과를 증대시키는 것으로 드러나, 서로 시너지 효과를 낼 수 있음이 여러 연구에서 보고되었습니다.

중추신경계-말초면역계 간 '염증 반사'로서의 신경 조절

신체 내 염증정보가 미주신경을 따라 연수의 연수 뒤핵(NTS)으로 전달되면, NTS에서의 신경 신호는 다시 말초의 면역 반응을 조절하는 순환 회로를 형성합니다.

이 신경 반사는 과도한 염증으로 인한 조직 손상을 억제하는 동시에, 적절한 면역 활성화를 유도하는 균형조절 기능을 수행합니다.

임상·전임상적 근거 및 연구 동향

유방암, 뇌종양(교모세포종) 쥐 모델에서 VNS가 IL-6 감소를 통한 염증억제 및 T세포 매개 항암면역 증강효과를 보였습니다.​

인간 임상시험에서 VNS는 면역억제적 시간 및 종양 조직을 면역 활성화 환경으로 변화시켜, 기존 항암 치료나 면역관문억제제와의 결합 치료 가능성도 탐색되고 있습니다.

최신 및 영향력 높은 주요 참고 자료
S Brem et al., "Vagus nerve stimulation: Novel concept for the treatment of cancer", ScienceDirect, 2024​

T Pu et al., "Neuro-immune crosstalk in cancer", Nature Communications, 2025​

WB Huang, "Vagal nerve activity and cancer prognosis", PubMed Central, 2025​

R Das, "Electrical Stimulation for Immune Modulation in Cancer", Front. Bioeng. Biotechnol., 2022​

요약하자면, 미주신경 자극치료는 inflammatory reflex 경로를 통해 암 종양 미세환경 내 염증 자극을 약화시키고, 면역세포 특히 T 세포와 NK 세포를 활성화하며, time(면역 미세환경의 시계성)을 조절해 암세포의 면역적 사멸을 증진시키는 최신 치료 접근법입니다.

최신 및 영향력 있는 논문들을 종합하면, 식물 발효 대사산물(plant fermentation metabolites)은 종양 면역 미세환경(TIME)의 circadian time 조절을 통해 PD-1/PD-L1 면역관문억제제 효과를 증진하고 암세포 사멸을 유도하는 기전은 다음과 같습니다:​

1. 면역대사 및 circadian 리듬 동기화
식물 발효 과정에서 생성되는 단쇄 지방산(SCFAs), 폴리페놀 대사산물, 트립토판 유도체 등은 종양 미세환경 내 면역세포의 시계유전자(CLOCK, BMAL1, PER 등)를 조절합니다.

이로 인해 염증성 사이토카인 분비, 면역세포(특히 CD8+ T 세포, NK 세포)의 활성화 및 침투가 시간에 따라 리듬성으로 조절되어 면역 반응이 최적화됩니다.​

2. 면역관문억제제와의 시너지
발효 대사산물들은 PD-1/PD-L1의 발현을 낮추거나, PD-1 차단제가 효과적으로 작용하도록 TME 내 면역억제적 세포(Treg, MDSC)의 숫자와 기능을 억제합니다.

특히, 특정 프로바이오틱스 유래 발효산물이 수용체 경로를 활성화해 항원제시세포(DC) 기능을 도와 CD8+ T 세포 활성화를 촉진, 항암 면역치를 증가시키면서 면역관문억제제의 효과를 강화합니다.​

3. 대사 리프로그래밍 및 종양세포 사멸 유도
암세포 및 면역세포의 대사 경로를 동기화·재조절하여, glycolysis, fatty acid oxidation, tricarboxylic acid cycle(TCA) 등을 정상화하거나 암세포 사멸 경로(apoptosis, ferroptosis)를 활성화합니다.

발효산물은 세포 내 epigenetic 변화를 유발해 항암유전자 및 면역 활성 유전자의 주기적 발현을 촉진함으로써 TME의 항암 환경을 조성합니다.​

4. 임상적·전임상 연구 동향
대표 논문은 식물 발효 대사산물이 항암 치료 중 면역관문억제제 반응률 개선, 부작용 완화, 환자의 종양 성장 억제와 생존율 향상에 기여함을 증명했습니다.

장내 미생물 조절과 발효산물 보충을 통해 TIME 내 circadian 리듬을 재설정하는 전략이 치료 저항성 극복에 관건임을 강조합니다.

---

요약: 식물 발효 대사산물은 TME 내 면역세포의 circadian 시간이 조절되어 PD-1/PD-L1 면역관문 억제제와 결합 시 항암면역 반응을 극대화하며, 대사 및 epigenetic 경로를 통한 암세포 사멸 촉진을 통해 종양의 진행을 억제하는 최신 면역 항암 치료 보조제 역할을 합니다.​

논문명/저자저널/출판연도주요 내용

Xie M. et al. "The gut microbiota in cancer immunity and immunotherapy"	Front. Immunol. 2025	발효 대사산물이 면역세포 활성 및 PD-1 치료효과 증진 기전​
Zhu Q. et al. "Innovative strategies to enhance cancer immunotherapy"	Cancer Res. Reviews, 2025	식물 화합물과 면역관문억제제 시너지​
Lim SA. "Metabolic reprogramming of the tumor microenvironment"	Nat Rev Cancer 2024	TME 대사 및 circadian 영향 상세 설명​
Liu J et al. "Microbial metabolites involved in tumorigenesis and immune regulation"	Front. Immunol. 2023	SCFA, 트립토판 대사 및 면역기능 조절​
Li J. "Circadian Rhythms in Tumor Regulation"	ERHM 2025	CLOCK, BMAL1 등 시계유전자 기반 면역 시간 조절​

종양 세포는

생존과 증식을 보장하기 위해 해당 분자를 발현하여

신경 세포의 항염증 프로파일을 모방함으로써 면역 감시를 회피할 수 있다.

이러한 분자적 유사성으로 인해,

신경계를 표적으로 삼은 면역계의 공격은 신경학적 손상을 초래하고

환자 상태를 악화시키며 사망률을 높일 수 있다.

To ensure their survival and proliferation,

tumor cells can mimic the anti-inflammatory profiles of neuronal cells

by expressing corresponding molecules to evade immune surveillance.

Owing to these molecular similarities,

the immune system’s targeted attack on the nervous system

can lead to neurological damage, exacerbate patient conditions, and elevate mortality rates.

따라서 신경계와 면역계가

종양 미세환경(TME)을 어떻게 조율하고 조절하는지에 대한 상세한 이해는

암 예방 및 치료를 위한 새로운 관점과 방법을 제공할 수 있다.

본 리뷰에서는

면역계를 매개로 한 신경계와 종양 간의 양방향 상호작용을 탐구한

최근 연구에 초점을 맞춘다:

신경 활동이 종양 면역을 조절하는 방식과,

반대로 종양에 의한 면역 변화가 신경계 기능에 미치는 영향.

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Introduction

The nervous system, comprising the central and peripheral nerve systems, along with neurotransmitters and neuropeptides, extends nerve endings throughout the body’s tissues, excluding the stratum corneum.1 It not only modulates a broad spectrum of physiological processes, encompassing movement, perception, cognition, and responses to external stimuli.2 But also it’s responsible for maintaining the stability of vital signs and the homeostasis of immune status.3,4 The immune system, consisting of immune organs, cells, molecules, and lymphatic vessels, is similarly widespread and tasked with the identification and elimination of pathogens and tumor cells through antibody production and immune cell activation. The interplay between the nervous and immune systems is essential for homeostatic maintenance, which is pivotal in tumor prevention and control.5 While TME is typically considered the local environment surrounding tumor cells, which includes a complex ecosystem composed of tumor cells, immune cells, fibroblasts, endothelial cells, extracellular matrix (ECM), and secreted factors.6,7,8 Often overlooked, neural components within the TME are a critical part of this ecosystem.9 In fact, nerve endings extend into the TME,10 along with leukocytes that are present there, regulate the growth, invasion, and metastasis of tumor cells.11,12,13 Early in tumor development, the dysfunction of the nervous and immune systems can lead to a failure to promptly eliminate the tumor, providing it with an opportunity to continue growing. During the growth of the tumor, the nervous system may act as a sanctuary,14 and cytotoxic T cells may become exhausted.15,16 These factors can contribute to uncontrollable tumor growth. However, the precise mechanisms by which the nervous system governs and regulates the immune system are not yet fully understood in TME. This field has attracted growing attention in recent years.

소개

중추 신경계와 말초 신경계, 신경 전달 물질 및 신경 펩티드로 구성된 신경계는

각질 stratum corneum 을 제외한 신체 조직 전체에 신경 종말을 확장합니다. 1 

이는 운동, 지각, 인지 및 외부 자극에 대한 반응을 포괄하는

광범위한 생리학적 과정을 조절할 뿐만 아니라,2 

생체 신호의 안정성과 면역 상태의 항상성 유지에도 책임이 있습니다.3,4 

면역 기관, 세포, 분자 및 림프관으로 구성된 면역 체계 역시

광범위하게 분포되어 있으며,

항체 생산과 면역 세포 활성화를 통해

병원체와 종양 세포를 식별하고 제거하는 임무를 맡고 있습니다.

신경계와 면역계의 상호작용은 항상성 유지에 필수적이며,

이는 종양 예방 및 통제에 핵심적 역할을 합니다.5 

종양 미세환경(TME)은

일반적으로 종양 세포를 둘러싼 국소 환경으로 간주되며,

종양 세포, 면역 세포, 섬유아세포, 내피 세포, 세포외 기질(ECM), 분비 인자로 구성된

복잡한 생태계를 포함합니다.6,7,8 

종종 간과되지만,

TME 내 신경 구성 요소는 이 생태계의 중요한 부분입니다. 9 

실제로 신경 말단은

종양 미세환경(TME) 내부로 확장되며,10 

그곳에 존재하는 백혈구와 함께 종양 세포의 성장, 침윤 및 전이를 조절한다.11,12, 13 

종양 발달 초기 단계에서 신경계와 면역계의 기능 장애는

종양을 신속히 제거하지 못하게 하여

종양이 계속 성장할 기회를 제공합니다.

종양 성장 과정에서

신경계는 피난처 역할을 할 수 있으며,14 

세포독성 T 세포는 소진될 수 있습니다.15,16 

이러한 요인들은

통제 불가능한 종양 성장에 기여할 수 있습니다.

그러나

신경계가 종양 미세환경(TME) 내에서 면역계를 통제하고 조절하는 정확한 메커니즘은

아직 완전히 밝혀지지 않았다.

이 분야는

최근 몇 년간 점점 더 많은 관심을 끌고 있다.

The nervous system can sense the immune status within TME and relay this information to the brain, which integrates the incoming data and acts back on TME, forming a comprehensive neural circuit.17 Within this circuit, the sensory nerve and the vagus nerve are responsible for gathering immune information from TME and conveying it to the brain. After integrating the information, the brain can feed back to the immune system18 that can be activated to regulate leukocyte trafficking and function. This pathogenesis can influence the effectiveness of anti-cancer immunity or immunotherapeutic strategies.19 The brain can also regulate the immune status of tissues through the vagus or sympathetic nerves,20 such as limiting the secretion of inflammatory factors in experimental lipopolysaccharide (LPS)-induced sepsis.1 Furthermore, the brain can exert regulatory effects on TME through the hypothalamic–pituitary–adrenal (HPA) axis.21,22 The circadian rhythm and the gut-brain axis are also integral components in the nervous system’s regulation of the TME. The suprachiasmatic nucleus (SCN), situated in the anterior hypothalamus, serves as the pacemaker of rhythm, coordinating the rhythm of peripheral tissues through genetic and protein networks, ensuring harmonious physiological functioning.23 Current study is increasingly focusing on the gut-brain axis, where the intestinal tract, enriched with neural and immune components, plays a significant role in tumor immunity through its interactions with the gut microbiota.24 Intriguingly, tumors can also exert substantial influence on the nervous system through the immune system, indicating a bidirectional relationship.25

Therefore, a detailed understanding of the mechanisms by which the nervous and immune systems interact in cancer is extremely important for both the prevention and treatment of cancer. In this review, we summarize the interplay between the nervous and the immune systems in the TME.

신경계는

TME 내 면역 상태를 감지하고 이 정보를 뇌로 전달할 수 있으며,

뇌는 들어오는 데이터를 통합하여

TME에 다시 작용함으로써 포괄적인 신경 회로를 형성한다.17

이 회로 내에서 감각 신경과 미주 신경은

TME로부터 면역 정보를 수집하여 뇌로 전달하는 역할을 담당한다.

정보를 통합한 후,

뇌는 백혈구 이동 및 기능을 조절하기 위해 활성화될 수 있는 면역 체계에 피드백할 수 있습니다.18

이러한 병리 기전은 항암 면역 또는 면역 치료 전략의 효과에 영향을 미칠 수 있습니다.19 뇌는 또한 미주신경이나 교감신경을 통해 조직의 면역 상태를 조절할 수 있으며,20 예를 들어 실험적 리포폴리사카라이드(LPS) 유발 패혈증에서 염증 인자의 분비를 제한하는 등의 역할을 합니다.1 또한, 뇌는 시상하부-뇌하수체-부신(HPA) 축을 통해 종양 미세환경(TME)에 조절 효과를 발휘할 수 있습니다.21,22 일주기 리듬과 장-뇌 축 역시 신경계가 TME를 조절하는 데 있어 필수적인 구성 요소입니다. 시상하부 전엽에 위치한 시상하부 시계핵(SCN)은 리듬의 박동조절기 역할을 하며, 유전자 및 단백질 네트워크를 통해 말초 조직의 리듬을 조정하여 조화로운 생리 기능을 보장한다. 23 최근 연구는 신경 및 면역 구성 요소가 풍부한 장관이 장내 미생물군과의 상호작용을 통해 종양 면역에 중요한 역할을 하는 장-뇌 축에 점점 더 주목하고 있다.24 흥미롭게도 종양 또한 면역계를 통해 신경계에 상당한 영향을 미칠 수 있어 양방향 관계를 시사한다.25

따라서

암에서 신경계와 면역계가 상호작용하는 메커니즘을 상세히 이해하는 것은

암 예방과 치료 모두에 극히 중요하다.

본 리뷰에서는

종양 미세환경(TME) 내 신경계와 면역계의 상호작용을 종합한다.

Neuroregulation of the immune system

The nervous and immune systems are often described and studied as distinct entities,26 however, over the past few decades, numerous studies have reported that hematopoietic and lymphatic organs have abundant neural innervation, which greatly facilitates the exchange between nerves and leukocytes.27,28,29 Calcitonin gene-related peptide (CGRP) sensory and sympathetic nerve innervation have been confirmed in lymph nodes,30,31,32,33,34 spleen35,36,37 (Fig. 1), bone marrow,38,39,40,41, and thymus.42,43 CGRP is present in the thymus, although there is no direct evidence to confirm‎ its release by CGRP neurons.42 Adrenergic nerve controls blood vessels or directly modulates the function of lymph nodes through the norepinephrine (NE)/β1 and β2-adrenergic receptor axis.44,45,46,47,48,49,50 A Study has reported that the brain’s reward system can diminish the immunosuppressive function of bone marrow-derived suppressive cells (MDSCs) in the bone marrow by activating the sympathetic nervous system, thereby slowing tumor growth.51 For a long time, it has been uncertain whether the immune organs are innervated by the parasympathetic nervous system,36,39,43,52,53,54 but recently, a study shows that the spleen has direct parasympathetic innervation55 (Fig. 1).

면역계의 신경조절

신경계와 면역계는 종종 별개의 실체로 기술되고 연구되지만,26 지난 수십 년간 수많은 연구에서 조혈 및 림프 기관에 풍부한 신경 분포가 존재하여 신경과 백혈구 간의 교류를 크게 촉진한다는 사실이 보고되었다.27,28,29 칼시토닌 유전자 관련 펩타이드(CGRP) 감각 및 교감 신경 분포가 림프절,30,31,32, 33,34 비장35,36,37 (그림 1), 골수,38,39,40,41 및 흉선에서 확인되었다.42,43 CGRP는 흉선에 존재하지만, CGRP 신경세포에 의한 분비를 확인하는 직접적인 증거는 없다.42 아드레날린성 신경은 혈관을 조절하거나 노르에피네프린 (NE)/β1 및 β2-아드레날린성 수용체 축을 통해 림프절의 기능을 직접 조절합니다.44,45,46,47,48,49,50 한 연구에 따르면, 뇌의 보상 시스템은 교감신경계를 활성화하여 골수 내 골수유래억제세포(MDSCs)의 면역억제 기능을 감소시켜 종양 성장을 늦출 수 있다고 보고되었습니다. 51 오랫동안 면역 기관이 부교감 신경계에 의해 신경 분포되는지 여부는 불확실했습니다.36,39,43,52,53,54 그러나 최근 연구에 따르면 비장은 직접적인 부교감 신경 분포를 가지고 있습니다.55 (그림 1).

Fig. 1

The neural innervation of the spleen. Spleen-innervating nociceptors, which originate from left T8 to T13 dorsal root ganglia and innervate the spleen along blood vessels to reach B cell zones, where nociceptor-derived CGRP promotes germinal center responses via the CALCRL-RAMP1 receptor on B cells. Activating these nociceptors with capsaicin enhances proliferation of germinal centers and plasma cells (PCs), increases secretion of antibody, improvement of humoral immunity, and host defense. The increased antibodies and CGRP entering the bloodstream may lead to elevated levels of antibodies in TME, thereby potentially influencing antitumor immunity. The splenic sympathetic nerves mainly originate from the T5 to T12 segments of the thoracic spinal cord, enter the spleen along the blood vessels, and innervate the spleen. The sympathetic nervous system releases NE, which interacts with the β2-AR present on macrophages. This interaction results in a reduced secretion of IL-1β and TNF-α. Additionally, NE influences ChAT+ CD4+ T cells, prompting them to release ACh. ACh binds to α7nAChR on macrophages, further contributing to the suppression of IL-1β and TNF-α release. Consequently, the diminished levels of these pro-inflammatory mediators in the bloodstream may modulate the body’s antitumor immune response as well as NE in the TME. The existence of parasympathetic innervation to the spleen is controversial, however, a recent study shows that there are parasympathetic nerves directly projected to the spleen. The presence of Ach and cocaine- and amphetamine-regulated transcript peptide (CARTp) within splenic tissues has been documented. Alterations in the blood concentrations of ACh and CARTp may modulate antitumor immunity. This figure was created with BioRender (https://biorender.com/)

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그림 1

비장의 신경 분포. 비장을 분포하는 통각 수용체는 왼쪽 T8부터 T13 후근 신경절에서 기원하여 혈관을 따라 비장에 도달하여 B 세포 영역에 이릅니다. 여기서 통각 수용체 유래 CGRP는 B 세포의 CALCRL-RAMP1 수용체를 통해 생식 중심 반응을 촉진합니다. 캡사이신으로 이러한 통각 수용체를 활성화하면 생식 중심과 형질 세포(PC)의 증식이 촉진되고, 항체 분비가 증가하며, 체액성 면역과 숙주 방어 기능이 향상된다. 증가된 항체와 CGRP가 혈류로 유입되면 종양 미세환경(TME) 내 항체 농도가 상승하여 항종양 면역에 잠재적으로 영향을 미칠 수 있다. 비장 교감신경은 주로 흉추 T5-T12 부위에서 기원하여 혈관을 따라 비장으로 진입하여 비장을 신경 분포한다. 교감신경계는 NE를 분비하며, 이는 대식세포에 존재하는 β2-AR과 상호작용한다. 이 상호작용은 IL-1β 및 TNF-α 분비를 감소시킨다. 또한 NE는 ChAT+ CD4+ T 세포에 영향을 주어 ACh 분비를 촉진합니다. ACh는 대식세포의 α7nAChR에 결합하여 IL-1β 및 TNF-α 분비 억제에 추가적으로 기여합니다. 결과적으로 혈류 내 이러한 전염증성 매개체의 감소된 수준은 신체의 항종양 면역 반응과 TME 내 NE를 조절할 수 있습니다. 비장 내 부교감 신경 분포의 존재는 논란의 여지가 있으나, 최근 연구에 따르면 비장으로 직접 투사되는 부교감 신경이 존재함이 밝혀졌다. 비장 조직 내 아세틸콜린(Ach)과 코카인-암페타민 조절 전사체 펩타이드(CARTp)의 존재가 확인되었다. 혈중 Ach 및 CARTp 농도의 변화는 항종양 면역 반응을 조절할 수 있다. 이 그림은 BioRender(https://biorender.com/)로 제작되었습니다.

The current understanding of the neural center that regulates the immune system is not yet clear. Some studies have found that when inflammation occurs in peripheral tissues, a group of cells in the insular cortex of the brain (InsCtx neurons) are activated.56 Inhibiting the InsCtx neurons can improve peripheral inflammation. In the absence of peripheral inflammation, stimulating the InsCtx neurons can reproduce the effects of peripheral inflammation. These cells project to areas controlled by the autonomic nervous system, such as the dorsal motor nucleus of the vagus (DMV) and the rostral ventrolateral medulla (RVLM).56

면역 체계를 조절하는 신경 중추에 대한 현재의 이해는 아직 명확하지 않습니다. 일부 연구에 따르면 말초 조직에서 염증이 발생하면 뇌의 섬피질(InsCtx 뉴런)에 있는 세포 집단이 활성화됩니다.56 InsCtx 뉴런을 억제하면 말초 염증을 개선할 수 있습니다. 주변 염증이 없는 상태에서 InsCtx 뉴런을 자극하면 주변 염증의 효과를 재현할 수 있다. 이 세포들은 미주신경의 등측 운동핵(DMV) 및 전측 복측 수질(RVLM)과 같이 자율신경계가 제어하는 영역으로 투사된다.56

Studies on neuro-immune circuits are still relatively limited. It was discovered that the vagus nerve, upon sensing peripheral inflammation, activates the caudal Nucleus of the Solitary Tract (cNST) and the Area Postrema (AP), suggesting that these may be the sensory nuclei for immune regulation.18 Another study reported that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN), which contain corticotropin-releasing hormone (CRH), are connected to the splenic nerve via the sympathetic nervous system.57 It has been demonstrated that motor circuits rapidly mobilize neutrophils from bone marrow to peripheral tissues by neutrophil-attracting chemokines derived from skeletal muscle. In contrast, PVN controlled the migration of monocytes and lymphocytes from secondary lymphoid organs and blood to the bone marrow via direct, cell-intrinsic glucocorticoid (GC) signaling.58 A similar response has been observed in breast cancer, where tumor burden leads to widespread anxiety in mice. The activation of CRH neurons in CeA led to the proliferation of sympathetic fibers in the breast cancer TME, promoting tumor growth.59 The reduction of sympathetic nerves in TME and the slowing of tumor growth was achieved by pharmacological or genetic blockade of the CRH neurons in the CeA to the lateral paragigantocellular nucleus (LPGi) circuit. Furthermore, the use of alprazolam, an anti-anxiety medication, hindered the growth of breast cancer.59,60

Based on the aforementioned studies,18,56,57,58,59 we can summarize several neural-immune-cancer circuits (Fig. 2). They follow the neural reflex pattern of sense-neural center-effect. Afferent nerves detect inflammatory signals within TME,18 conveying them to the neural center,56 which then integrates this information and feeds back to TME via efferent nerves.59,60 However, in different tissues, the pathways of neuro-immune-cancer circuitry may vary because the distribution of nerves in the skin, muscles, and viscera is distinct. Consequently, the neuro-immune regulation of tumors in different locations may also differ. These neuro-immune-cancer circuits require more experimental validation.

신경-면역 회로에 대한 연구는 아직 상대적으로 제한적이다. 미주신경이 말초 염증을 감지하면 고립신경로 꼬리핵(cNST)과 후부역전핵(AP)을 활성화한다는 사실이 발견되었으며, 이는 이들이 면역 조절을 위한 감각핵일 수 있음을 시사한다.18 또 다른 연구에서는 편도체 중심핵(CeA)의 뉴런과 코르티코트로핀 방출 호르몬(CRH)을 포함하는 시상하부 시상핵(PVN)이 교감신경계를 통해 비장신경과 연결되어 있음을 보고하였다.57 편도체 중심핵(CeA)의 뉴런은 시상하부 시상핵(PVN)과 연결되어 있으며, 이 두 부위는 교 (CeA) 및 시상하부 시상핵(PVN)의 뉴런이 교감신경계를 통해 비장신경과 연결되어 있음을 보고하였다.57 운동 회로가 골격근에서 유래된 호중구 유인 케모카인을 통해 골수에서 말초 조직으로 호중구를 신속히 동원한다는 것이 입증되었다. 반면, PVN은 직접적인 세포 내 글루코코르티코이드(GC) 신호전달을 통해 이차 림프기관 및 혈액에서 단핵구와 림프구의 골수 이동을 조절했다.58 유방암에서도 유사한 반응이 관찰되었는데, 종양 부하가 생쥐에서 광범위한 불안을 유발했다. CeA 내 CRH 뉴런의 활성화는 유방암 TME 내 교감 신경 섬유의 증식을 유발하여 종양 성장을 촉진했다.59 CeA에서 측방 거대세포핵(LPGi) 회로로 연결되는 CRH 뉴런을 약리학적 또는 유전적으로 차단함으로써 TME 내 교감 신경 감소와 종양 성장 지연을 달성했다. 또한 항불안제인 알프라졸람 사용은 유방암의 성장을 방해했다.59,60

상기 연구들,18,56,57,58,59를 바탕으로 신경-면역-암 회로들을 몇 가지 요약할 수 있다(그림 2). 이들은 감각-신경중심-효과라는 신경 반사 패턴을 따른다. 구심성 신경은 종양 미세환경(TME) 내 염증 신호를 감지하여18 신경 중추로 전달하며,56 신경 중추는 이 정보를 통합하여 원심성 신경을 통해 TME로 피드백한다.59,60 그러나 피부, 근육, 내장 등 조직마다 신경 분포가 다르므로 신경-면역-암 회로의 경로도 달라질 수 있다. 결과적으로 위치에 따른 종양의 신경-면역 조절도 차이가 있을 수 있다. 이러한 신경-면역-암 회로에 대해서는 더 많은 실험적 검증이 필요하다.

Fig. 2

Neuro-immune-cancer circuits. Sensory nerves detect signal molecules (such as inflammatory mediators, MMPs, DAMPs) within TIME, leading to the release of CGRP and transmission of signals to the dorsal horn of the spinal cord. Subsequently, the signals are relayed through the spinothalamic tract to the ventral nucleus of the thalamus (VPL), where the signals are further conveyed to neurons within InsCtx. The response signals are then transmitted to CeA and PVN from InsCtx, followed by projections to LPGi, and then transmitted to sympathetic nerves, which modulate the TIME through NE. Vagus nerves can also detect signal molecules within TIME, and transmit these molecules to the cNST and AP. The signals are then relayed to neurons within InsCtx, and the response signals are transmitted to DMV and RVLM, ultimately returning to the TIME via the vagus nerves. In addition, sensory nerves detect signal molecules within the TIME, leading to the release of CGRP and signal transmission to the dorsal horn of the spinal cord, followed by transmission through the spinothalamic tract to VPL. The signals continue to neurons within InsCtx, subsequently the response signals are transmitted to DMV/RVLM, and then relayed to vagus nerves that modulate TIME via Ach. Furthermore, vagus nerves detect signal molecules within TIME, transmit signals to cNST and AP, and then relayed to neurons within InsCtx, followed by the transmission of response signals to the CeA/PVN, leading to increased activity in LPGi. Ultimately, the signals are transmitted to sympathetic nerves that modulate TIME through NE. Moreover, PVN is a key brain region in activating the HPA axis, controlling immune responses through the release of GCs and CAs from the adrenal glands. This figure was created with BioRender (https://biorender.com/)

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그림 2

신경-면역-암 회로. 감각 신경은 TIME 내 신호 분자(염증 매개체, MMPs, DAMPs 등)를 감지하여 CGRP 방출을 유도하고 신호를 척수 후각으로 전달한다. 이후 신호는 척수시상로를 통해 시상 복측핵(VPL)로 전달되며, 여기서 신호는 InsCtx 내 뉴런으로 추가 전달된다. 반응 신호는 InsCtx에서 CeA 및 PVN으로 전달된 후 LPGi로 투사되고, 교감 신경으로 전달되어 NE를 통해 TIME을 조절한다. 미주 신경 또한 TIME 내 신호 분자를 감지하여 이를 중추신경계(cNST) 및 자율신경계(AP)로 전달한다. 신호는 InsCtx 내 뉴런으로 전달되며, 반응 신호는 DMV 및 RVLM으로 전달된 후 미주신경을 통해 TIME으로 되돌아간다. 또한 감각신경은 TIME 내 신호 분자를 감지하여 CGRP 방출을 유발하고, 이 신호는 척수 후각으로 전달된 후 척수시상로를 통해 VPL로 전달된다. 신호는 InsCtx 내 신경세포로 계속 전달되며, 이후 반응 신호는 DMV/RVLM으로 전달된 후 부교감신경(Ach)을 통해 TIME을 조절하는 미주신경으로 중계됩니다. 또한 미주신경은 TIME 내 신호 분자를 감지하여 cNST 및 AP로 신호를 전달하고, 이후 InsCtx 내 신경세포로 중계된 후 반응 신호가 CeA/PVN으로 전달되어 LPGi의 활동 증가를 유발합니다. 궁극적으로 신호는 교감신경으로 전달되어 노르에피네프린(NE)을 통해 TIME을 조절합니다. 또한 시상하부 시상핵(PVN)은 부신에서 글루코코르티코이드(GC)와 카르티코스테로이드(CA)를 분비하여 면역 반응을 제어하는 HPA 축 활성화의 핵심 뇌 영역입니다. 본 그림은 BioRender(https://biorender.com/)로 제작되었습니다.

Neuro-immune regulation of central nervous system (CNS) tumors

Immune surveillance in the meninges

The traditional view holds that the CNS is an immunologically privileged organ, due to the presence of the blood–brain barrier (BBB) and an absence of lymphatic vessels.61 However, a recent study discovered the existence of functional lymphatic vessels within the CNS. These vessels are located near the dural sinuses, express lymphatic endothelial cell markers, and can carry cerebrospinal fluid (CSF) and immune cells. They are closely related to the circulation of CSF and are connected to the deep cervical lymph nodes.62 CSF exchanges with the brain’s interstitial fluid, aiding in the clearance of metabolic waste from the brain, such as amyloid-beta (Aβ). The CSF, carrying antigens and waste, circulates through the ventricles, cisterns, the central canal, and the subarachnoid space, with the lymphatic vessels responsible for collecting CSF and large molecular substances, including antigens, transporting them to the deep cervical lymph nodes to activate an immune response.63

Immune cells of the CNS originate not only from the blood supply of the heart but also from the skull marrow. The skull marrow produces a variety of immunocytes, including B cells, monocytes, and neutrophils that can migrate to the meninges through direct channels between the skull and the meninges, and even enter the CNS parenchyma in pathological states.64 The meninges contain diverse immunocytes, including macrophages, dendritic cells (DCs), T cells, and B cells, which can directly contact CSF, monitor, and respond to pathological changes in the CNS. Researchers have discovered “arachnoid capillary exits” points, which allow the exchange of CSF and molecules between the subarachnoid space and the dura mater.63 Immune cells in the meninges can also support humoral immunity of the meninges through organized lymphoid-like structures (dural-associated lymphoid tissues, DALT). Particularly, the rostral-rhinal venolymphatic hub structure, which surrounds the anterior part of the sinuses and the nasal confluence, includes lymphatic vessels that can sample antigens and rapidly support humoral immune responses.65 When the CNS is infected or damaged, the levels of inflammatory factors and antigens in the CSF will rise and these changes can activate immune cells in the meninges which can migrate to the lymph nodes through the lymphatic vessel system, initiating a broader immune response, such as the production of antibodies and activation of T cells.65

Immune surveillance in the brain

The immune functions within the brain are regulated by microglia. Microglia can be polarized into either a pro-inflammatory (M1-type microglia) or an anti-inflammatory and tissue repair (M2-type microglia) state.66 In response to pathogens, microglia activate T cells and secrete inflammatory factors, including TNF-α, IL-6, and IL-1β.67 Subsequently, to mitigate this response, T cells release cytokines such as IL-4 and IL-13, which help to shift microglia from the M1 to the M2 phenotype.68 In the immune system, helper T (Th) cells are T lymphocytes that produce cytokines. Th1 cells generate pro-inflammatory cytokines, while Th2 cells produce anti-inflammatory factors, including IL-10.69

중추신경계(CNS) 종양의 신경-면역 조절

뇌막에서의 면역 감시

전통적인 관점은 혈뇌장벽(BBB)의 존재와 림프관의 부재로 인해 CNS가 면역학적으로 특권화된 기관이라고 주장해왔다.61 그러나 최근 연구에서 CNS 내 기능적 림프관의 존재가 발견되었다. 이 혈관은 경막동 근처에 위치하며 림프관 내피 세포 표지자를 발현하고 뇌척수액(CSF)과 면역 세포를 운반할 수 있습니다. 이들은 CSF 순환과 밀접하게 관련되어 있으며 심부 경부 림프절과 연결됩니다.62 CSF는 뇌의 간질액과 교환되어 아밀로이드 베타(Aβ)와 같은 뇌의 대사성 노폐물 제거를 돕습니다. 항원과 노폐물을 운반하는 CSF는 뇌실, 뇌척수액 주머니, 중앙관, 지주막하 공간을 순환하며, 림프관은 CSF와 항원을 포함한 고분자 물질을 수집하여 깊은 경부 림프절로 운반하여 면역 반응을 활성화하는 역할을 담당한다.63

중추신경계의 면역 세포는 심장의 혈액 공급뿐만 아니라 두개골 골수에서도 기원합니다. 두개골 골수는 B 세포, 단핵구, 호중구 등 다양한 면역 세포를 생성하며, 이들은 두개골과 뇌막 사이의 직접적인 통로를 통해 뇌막으로 이동할 수 있고, 병리학적 상태에서는 중추신경계 실질까지 침투할 수 있습니다. 64 수막에는 대식세포, 수지상 세포(DC), T 세포, B 세포 등 다양한 면역세포가 포함되어 있으며, 이들은 뇌척수액과 직접 접촉하여 중추신경계의 병리학적 변화를 감시하고 반응할 수 있습니다. 연구자들은 지주막하 공간과 경막 사이에서 뇌척수액과 분자의 교환을 가능하게 하는 “거미막 모세혈관 출구” 지점을 발견했습니다.63 수막의 면역 세포는 또한 조직화된 림프구 유사 구조(경막 관련 림프 조직, DALT)를 통해 수막의 체액성 면역을 지원할 수 있습니다. 특히, 부비동과 비강 합류부 전부를 둘러싸고 있는 전두-비강 정맥림프 허브 구조는 항원을 채취하고 체액성 면역 반응을 신속하게 지원할 수 있는 림프관을 포함하고 있습니다. 65 중추신경계가 감염되거나 손상되면 뇌척수액 내 염증 인자와 항원 수치가 상승하며, 이러한 변화는 뇌막 내 면역 세포를 활성화시켜 림프관 시스템을 통해 림프절로 이동하게 하여 항체 생성 및 T 세포 활성화와 같은 광범위한 면역 반응을 유발할 수 있습니다.65

뇌 내 면역 감시

뇌 내 면역 기능은 미세아교세포에 의해 조절됩니다. 미세아교세포는 염증 촉진형(M1형 미세아교세포) 또는 항염증 및 조직 복구형(M2형 미세아교세포) 상태로 분극될 수 있다.66 병원체에 반응하여 미세아교세포는 T 세포를 활성화하고 TNF-α, IL-6, IL-1β 등의 염증 인자를 분비한다.67 이후 이 반응을 완화하기 위해 T 세포는 IL-4 및 IL-13과 같은 사이토카인을 방출하여 미세아교세포를 M1 표현형에서 M2 표현형으로 전환하는 데 도움을 줍니다.68 면역 체계에서 헬퍼 T(Th) 세포는 사이토카인을 생성하는 T 림프구입니다. Th1 세포는 염증 촉진성 사이토카인을 생성하는 반면, Th2 세포는 IL-10을 포함한 항염증 인자를 생성합니다.69

Immune cells-glioma crosstalk

Tumors originating from the CNS encompass a spectrum of neoplasms, among which gliomas are the most preval‎ent. Gliomas arise from the glial cell lineage, specifically from astrocytes, oligodendrocytes, and ependymal cells, which are distinct glial cell types of the CNS.70,71,72 Utilizing gliomas as a paradigm, we delve into the intricate interplay of neuro-immune-cancer crosstalk, a dynamic and pivotal area of research within the scientific community.

During gliomagenesis, the BBB is compromised, allowing circulating T cells, B cells, macrophages, and MDSCs to cross the BBB.73 The reciprocal signaling between immunocytes and glioma cells establishes an immunosuppressive microenvironment to foster tumor growth74 (Fig. 3). From a 3D spatial perspective, different regions of the tumor may have varying densities of immune cells, such as T cells, B cells, natural killer (NK) cells, DCs, microglia, and macrophages, with some areas being densely populated and others relatively sparse.75 CD4+ and CD8+ T cells show different distribution patterns in various regions of the tumor. TME contains immunosuppressive cells, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), which are unevenly distributed across the tumor, affecting the immune response. Immune cells display different activation or exhaustion statuses in various regions of the tumor. For instance, T cells in the central region of the tumor are exhausted due to hypoxia and nutrient deficiency, while T cells at the tumor periphery are more active.75

면역 세포-교종 상호작용

중추신경계(CNS)에서 기원한 종양은 다양한 신생물 스펙트럼을 포함하며, 그중 교종이 가장 흔합니다. 교종은 신경교 세포 계통, 특히 중추신경계의 고유한 신경교 세포 유형인 성상세포, 올리고도교세포 및 뇌실상피세포에서 발생합니다.70,71,72 교종을 패러다임으로 삼아, 과학계 내에서 역동적이고 핵심적인 연구 분야인 신경-면역-암 상호작용의 복잡한 역학 관계를 탐구합니다.

교종 발생 과정에서 혈뇌장벽(BBB)이 손상되어 순환하는 T 세포, B 세포, 대식세포 및 골수유래억제세포(MDSC)가 BBB를 통과할 수 있게 된다.73 면역세포와 교종 세포 간의 상호 신호 전달은 종양 성장을 촉진하는 면역억제성 미세환경을 조성한다74 (그림 3). 3차원 공간적 관점에서, 종양의 서로 다른 영역은 T 세포, B 세포, 자연살해(NK) 세포, DC, 미세아교세포 및 대식세포와 같은 면역 세포의 밀도가 다양할 수 있으며, 일부 영역은 밀집되어 있고 다른 영역은 상대적으로 드문드문 분포할 수 있습니다.75 CD4+ 및 CD8+ T 세포는 종양의 다양한 영역에서 서로 다른 분포 패턴을 보입니다. 종양 미세환경(TME)에는 조절 T 세포(Tregs) 및 종양 연관 대식세포(TAMs)와 같은 면역억제 세포가 포함되어 있으며, 이들은 종양 전체에 고르지 않게 분포되어 면역 반응에 영향을 미칩니다. 면역 세포는 종양의 다양한 영역에서 서로 다른 활성화 또는 소진 상태를 보입니다. 예를 들어, 종양 중심부의 T 세포는 저산소증과 영양 결핍으로 인해 소진된 반면, 종양 주변부의 T 세포는 더 활발합니다.75

Fig. 3

Neuro-immune crosstalk in CNS tumors. Glioma-associated microglia and macrophages are attracted to the glioma. The metabolism of gliomas can produce a large amount of lactate, which promotes the transformation of microglia and macrophages into M2-type TAMs that suppress antitumor immunity and support tumor growth. Activated microglia secrete IL-10 and CCL5, supporting tumor formation and growth. Midkine activates CD8+ T cells, which produce CCL4, stimulating microglia to produce CCL5, CCL5 is crucial for the stem cells of low-grade glioma to survive and grow. IL-2 and IFN-γ boost T and NK cell growth/activation, enhancing immune surveillance of cancer cells. The inhibition of NK cell function in brain tumors may be partly due to the increased levels of TGF-β in the plasma. Elevated Tregs in gliomas produce IL-10 and TGF-β, promoting tumor growth. MDSCs adapt to the TME and suppress T cells via molecules like PD-L1, IL-10, and TGF-β. B lymphocytes express PD-L1, which engages with the PD-1 on T cells, resulting in T cell exhaustion and facilitating glioma evasion. Additionally, these B lymphocytes generate IL-10 and TGF-β, which dampen the activity of immune cells, including T cells and NK cells. Furthermore, they release VEGF, CXCL12, and CXCL13, promoting the formation of new blood vessels to nourish the glioma. Glioma cells are capable of upregulating thrombospondin-1 in DCs, which inhibits their maturation and biases cytokine secretion toward a Th2 profile, thereby potentially inducing a state of immunosuppression. This figure was created with BioRender (https://biorender.com/)

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Glioma-associated microglia and macrophages are attracted to the tumor,76 where they are polarized into M2-like cells that suppress tumor immunity and support tumor growth.77,78 Activated microglia secrete cytokines and growth factors that promote the growth and angiogenesis of tumor cells, such as IL-10, epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF).76 Microglia can also express the chemokine CCL5, which facilitates the proliferation and survival of oligodendrocyte precursor cells (OPCs), thereby supporting tumor formation and growth. Activated T cells secrete soluble factors that stimulate microglia to express CCL5, thus providing a supportive microenvironment for the engraftment of OPCs. In mice with a genetic deletion of Ccl5, OPCs fail to form tumors. These findings suggest that interventions targeting the interaction between T cells and microglia/macrophages could offer new strategies for the treatment of low-grade gliomas.79 Lactate produced by glioma cells can induce the polarization of TAMs toward the M2 phenotype. High-mobility group box 1 secreted by TAMs can promote the proliferation, migration, invasion, and mesenchymal transition of glioma cells.80 Lactate dehydrogenase A (LDHA) modulates the behavior of macrophages by regulating the metabolism and secretory signals of tumor cells, thereby promoting the progression of glioblastoma. Targeting LDHA or its downstream signaling pathways may provide new therapeutic strategies for glioblastoma.81 Although microglia are important in tumor immune suppression, recent studies show that macrophages from blood monocytes (MDMs) are the main immune suppressors in glioblastoma multiforme (GBM), rather than microglia. MDMs in GBM have high glycolysis linked to their suppressive role. GBM factors boost MDM glycolysis, lactate production, and IL-10, which supports T cell suppression through histone lactylation. GBM also activates the PERK-ATF4 pathway in MDMs, increasing GLUT1 for more glycolysis. Removing PERK in MDMs can stop histone lactylation, increase T cells in tumors, slow tumor growth, and enhance GBM treatment with immunotherapy. Targeting PERK to counteract histone lactylation could improve immunotherapy for GBM.82 Chronic stress can advance GBM by reducing immune cells in tumors, especially M1 macrophages and CD8+ T cells. It hinders the secretion of CCL3/4, affecting M1 macrophage recruitment. But adding CCL3 can improve the immunosuppressive environment and fight GBM progression caused by stress. It has been confirmed that CCL3 boosts the efficacy of immune checkpoint therapy in GBM.83 A subset of TAMs, termed lipid-laden macrophages, exhibit an immunosuppressive phenotype and meet the high metabolic demands of GBM by engulfing cholesterol-rich myelin debris, accumulating cholesterol, and directly transferring lipids to cancer cells to nourish them.84 In brain metastasis cancer, meningeal macrophages can secrete glial cell line-derived neurotrophic factor (GDNF) to aid breast cancer cells in surviving within the meninges, thereby promoting metastasis, depending on the binding of integrin α6 to laminin.85

NK cells are a component of the innate immune system, capable of killing tumor cells without prior sensitization. IL-2 and IFN-γ enhance the surveillance of cancer cells by the immune system by promoting the growth and activation of T cells and NK cells.86,87,88,89 In contrast, the downregulation of NK cell function in gliomas may be partly due to the increased levels of TGF-β and IL-10 in the plasma90,91 (Fig. 3), activating ligand downregulation and inhibitory ligand overexpression‎.92 Similar to other immunocytes, NK cells are also inhibited in GBM by upregulation of immune checkpoint molecules and the accumulation of immunosuppressive cells.93

T cells play a crucial role in antitumor immunity, especially CD8+ T cells. They are present within the TME of GBM. However, their activity is often compromised by a variety of mechanisms,94 such as tumor-induced immune checkpoint activation, T cell exhaustion, and infiltration by Tregs.95 Additionally, tumor cells release immunosuppressive cytokines, including TGF-β, which inhibit T cell activity.96 Midkine, identified as a factor produced by NF1-mutated neurons, can activate T cells, particularly CD8+ T cells. They produce CCL4, which consequently in turn acts on microglia, prompting them to release CCL5, which is crucial for the stem cells of low-grade glioma to survive and grow.97 This study suggests that CD8+ T cells are not always beneficial in killing tumor cells. Based on T cell subtype, their functional status, along with cytokines in TME, infiltrating T cells exhibit protumorigenic and antitumorigenic properties.98

Tregs are demonstrated to enhance the progression of GBM via suppressing antitumor immunity and establishing an immunosuppressive environment.99 An increase in the number of Tregs in gliomas leads to the production of high levels of IL-10 and TGF-β91 (Fig. 3). Moreover, the quantity of Tregs correlates with the World Health Organization grading of brain tumors, and depleting Tregs in mouse glioma models can improve survival rates.91,100 Therefore, maintaining a balanced immune function and eliminating Tregs are crucial for preventing the genesis of brain tumors.

B lymphocytes are responsible for the production of antibodies and play a significant role in the adaptive immune response. They can express immunological checkpoints, including PD-L1, that communicate with PD-1 on T cells, resulting in T cell exhaustion as well as the immune evasion of GBM cells.101 They can also produce cytokines, including IL-10 and TGF-β, that restrain the function of immunocytes such as T cells and NK cells.102 Additionally, B lymphocytes can produce factors that promote angiogenesis, including VEGF, CXCL12, and CXCL13.103,104 B cells isolated from GBM patient samples were found to enhance the growth and metastasis of tumor cells by secreting growth factors, including insulin-like growth factor-1 and hepatocyte growth factor. Conversely, Chemokines produced by B cells, such as CXCL13, can influence the TME of GBM, which is associated with enhanced T cell infiltration and improved patient survival.105

MDSCs, though scarce in GBM, play a central role in promoting tumor progression, angiogenesis, invasion, and metastasis. They adapt to the TME and suppress T cells via molecules like PD-L1, IL-10, and TGF-β. MDSCs also secrete VEGF for new blood vessel formation, nourishing the tumor, and release matrix metalloproteinases (MMPs) to break down the extracellular matrix, aiding tumor invasion and metastasis.106

DCs are pivotal antigen-presenting cells that initiate antitumor immunity by capturing, processing, and presenting tumor antigens to T cells. They engage in bidirectional communication with tumor cells through cytokine and chemokine exchange, which can influence tumor growth and survival. For instance, glioma cells can upregulate thrombospondin-1 (TSP-1) in DCs, impairing their maturation and skewing cytokine secretion toward a Th2 profile, potentially inducing immunosuppression. Leveraging the immunostimulatory properties of DCs, DC-based vaccines, such as DCVax-L, have been developed to enhance the immune response against brain tumors.107

Neuron-immune cell-cancer cell crosstalk

The integration of optic nerve activity in regulating the immune response to cancer growth has been demonstrated in experiments conducted on mice with Nf1 optic gliomas.108 In addition to the light-induced, visually experience-dependent neuronal control of the growth of optic gliomas, the Nf1 mutation in neurons also increases the firing of spontaneous action potentials.108 This heightened excitability leads to the production of midkine, a heparin-binding growth factor, which acts on T cells to induce the secretion of CCL4.97 This, in turn, causes microglia to secrete CCL5, a key mitogen for glioma cells.109 A paradigm has been established in which neurons modulate immune cells to facilitate tumor growth; however, this avenue of research is currently underexplored and necessitates further investigation (Fig. 3).

Neuron-cancer cell crosstalk

Recent findings reveal that normal neurons in the dorsal raphe nucleus, which secrete serotonin, project to the cortex where ependymomas grow. Upon entering ependymoma cells, serotonin binds to histone H3, a protein intricately associated with DNA. Histone serotonylation can modulate tumor growth. In animal models, enhancement of histone serotonylation intensified the growth of ependymomas, whereas its inhibition attenuated tumor progression. This study primarily focuses on the interplay between neuronal signaling, histone modifications, and tumor growth. Although the study does not investigate the involvement of immune cells in the pathogenesis, however they may be indirectly affected.110 The interactions between neurons and cancer encompass a plethora of mechanisms.1,11 An in-depth exploration of these mechanisms is beyond the scope of the present review, since we focus on the neuro-immune-cancer axis.

Peripheral nerves regulate the tumor immune microenvironment

Sensory nerve

Sensory neurons are capable of sensing and modulating immune and inflammatory responses.111 Noxious stimuli cause the release of neuropeptides from peripheral nerve fibers, such as CGRP and substance P (SP).112 The signaling of SP is mediated via the neurokinin 1 receptor (NK-1R),113 and enhances the activity of bone marrow stem cells. SP or NK-1R boosts the survival of activated T cells, triggers macrophages to secrete pro-inflammatory cytokines, and facilitates neutrophil chemotactic and migratory capabilities induced by CCL5.113,114,115 However, in thyroid cancer, SP binding to NK-1R can promote cancer growth, prevent cell death, and increase cancer spread and blood vessel formation.116 SP can also promote tumor metastasis by activating Toll-like receptor 7 on breast cancer cells through the action of extracellular RNA.117

The CGRP has various effects on components of the immune system. It can exert inhibitory effects, negatively impact innate immune responses, reduce inflammatory tissue injury, protect the host, while also exhibiting pro-inflammatory properties, such as attracting eosinophils to areas of inflammation, enhancing the production of extracellular traps, and facilitating T cell attachment via β integrins regulating.118,119 In addition, the neuron excretion of CGRP causes a decrease in levels of cytokine within macrophages as well as DCs, thereby inhibiting antigen presentation to cytotoxic T lymphocytes (CTLs).120 After activation of cAMP-dependent protein kinase through downstream receptors, CGRP enhances the secretion of IL-10 and inhibits the nuclear factor κB (NF-κB) activity, afterward, reduces monocytes and the function of macrophages and group 2 innate lymphoid cells recruitment, which are key to both physiological hemostasis and the defense of mucosal barriers. A study has shown that CGRP reduced inflammation in mouse models of LPS-induced pulmonary damage; this mechanism is based on the regulation of macrophage polarization toward M2-type.120 CGRP decreased NLRP3 expression‎ in pro-inflammatory M1 macrophages, as well as the expression‎ of proIL-1βmRNA triggered by LPS. Molecules produced by M2 macrophages, such as IL-10, are involved in this skewed polarization after the release of IL-4.120 Sensory neurons can also collaborate with immune cells to influence host defense against lung infections and injuries, exacerbate allergic reactions, and their role in lung cancer warrants further investigation.121

Cranial nerves typically have branches distributed in head and neck cancers and are involved in the regulation of TME. Most of the branches originate from the trigeminal nerve.122 CGRP, along with αCGRP isomer, are the main synaptic transmitters in the trigeminal ganglion, utilized by nerves through RAMP1-GPCR interaction signaling.123,124 In oral cancer tissue samples, an increase in αCGRP+ neuron innervation has been found, alongside a plethora of RAMP1+, CGRP receptors, as well as lymphocytes infiltrated in TME.125 This suggests that αCGRP plays a significant role in modulating tumor-associated immunity through the RAMP1 signaling pathway, which can be implicated in both innate and adaptive immunity. In a syngeneic oral cancer model utilizing CGRP gene knockout (CGRP KO) mice, researchers observed a marked increase in the infiltration of CD4+ and CD8+ T lymphocytes, as well as NK cells, compared to wild-type (WT) controls. Furthermore, the CGRP KO group exhibited a notable reduction in tumor size relative to the WT mice, indicating that αCGRP signaling can hinder antitumor immune activity.126 Additionally, single-cell RNA sequencing (scRNA-seq) revealed increased expression‎ of RAMP1 in tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma (HNSCC) samples compared to healthy donor palatine tonsil tissues, particularly in CD3+ CD4+ FOXP3– T cells. Notably, no difference in RAMP1 levels was found between the blood monocytes from HNSCC patients and healthy donors, suggesting the presence of localized, tumor-specific neural modulation of leukocytes.126 In mice with melanoma, CGRP+ sensory neurons have been found to inhibit antitumoral immune function via the RAMP1 signal, prompting CD8+ T cells exhaustion within TIME. Pharmacologic blockade of RAMP1 or knockout of the transient receptor potential vanilloid 1 (TRPV1, a sensory neuron ion channel) caused a reduction of CGRP+ signaling in TME, leading to decreased T cell exhaustion, reduced cancer size, as well as extended overall survival rates.127 ScRNA-seq of human melanoma tissues illuminated that RAMP1+ CD8+ T cell exhibited higher levels of exhaustion compared to RAMP1− CD8+ T cells, and patients with higher intensity of RAMP1+ CD8+ T cells had poorer survival rates127 (Fig. 4). In the glucose-deprived environment, oral mucosal cancer tissue secreted nerve growth factor (NGF) via activation of c-Jun triggered by reactive oxygen species (ROS). This NGF modulated nociceptive sensory nerves, promoting the production of CGRP. CGRP induced protective autophagy in cancer cells by disrupting the interaction between mTOR and Raptor, mediated by Rap1. The study indicates that nutrient-deprivation therapies targeting glycolysis and angiogenesis may exacerbate the vicious cycle between cancer cells and nociceptive sensory nerves. The use of FDA-approved anti-migraine drugs to block CGRP can significantly enhance the efficacy of tumor starvation therapy.128 In another study, the enrichment of CGRP-positive nerves was also found to be associated with poor prognosis in oropharyngeal squamous cell carcinoma(OPSCC), suggesting that CGRP antagonists may improve patients’ quality of life after radiotherapy.129 Medullary thyroid cancer (MTC) is a neuroendocrine tumor, it is reported that CGRP is highly expressed in MTC cells, which is linked to poorer disease-free survival. CGRP interacts with its receptor complex, including CALCRL and RAMP1 on DCs, leading to increased Kruppel-Like Factor 2 expression‎. This interaction disrupts the development of DCs, which are crucial for antitumor immune responses.130 In contrast to the aforementioned studies, CGRP can promote the differentiation of Th1 and Tc1 cells while inhibiting Th2 cell differentiation by activating RAMP3. In a mouse model of LCMV Armstrong virus infection, CGRP was shown to be necessary for enhancing antigen-specific Th1 and Tc1 responses. Mice deficient in CGRP (Calca−/−) exhibited weakened Th1 and Tc1 responses and reduced viral clearance capabilities following infection. This study suggests that the CGRP-RAMP3 axis may enhance T cell-specific tumor-killing functions, but further experiments are needed to confirm‎ this.131

Fig. 4

The TIME is regulated by peripheral nerves. Nociceptor neurons interact with melanoma cells, leading to the release of CGRP from nociceptor neurons. CD8+ T cells express the CGRP receptor RAMP1. CGRP, by binding to RAMP1, directly increases the exhaustion of cytotoxic CD8+ T cells. CGRP significantly enhances the expression‎ of IL-10, a marker of IL-4-induced M2-type macrophages. In a syngeneic oral cancer model using CGRP gene knockout (CGRP KO) mice, a higher infiltration of CD4+ and CD8+ T lymphocytes and NK cells was observed compared to the control group. NE enhances primary T cells differentiation into Tregs, which prevents effective antitumor immunity and favors further cancer growth and progression. Myeloid cells secrete IL-8 and IL-6 to promote tumor growth. In addition, activation of β-AR can promote cancer growth via secretion of immunosuppressive factors like VEGF, MMP, prostaglandin-endoperoxide synthase 2, IL-6, and TGF-β from macrophages. Blocking β-AR signaling enhances the generation of tumor antigen-specific CD8+ T cells in the tumor-draining lymph nodes and increases the frequency of tumor-infiltrating CD8+ T cells. Cholinergic activation of mAchR+ macrophages and TNF-α secretion inhibits tumor growth. The vagus nerve and TFF2-expressing Tms are suggested to prevent cancer progression. This figure was created with BioRender (https://biorender.com/)

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Sympathetic nerve

NE is the most common neurotransmitter released by sympathetic nerves. NE has a significant impact on TIME which is still a matter of controversy.132 Myeloid cells, including TAMs, tumor-associated DCs, and MDSCs, are influenced by environmental stress. Cancer cells as well as stromal cells possess adrenergic receptors (ARs), which enhance their resistance against immune cell-mediated killing and apoptosis. β-AR activation promotes the secretion of immunomodulatory cytokines, including IL-8 and IL-6, by cancer cells and myeloid cells.133,134,135 In addition, activation of β-AR can promote cancer growth via secretion of immunosuppressive factors like VEGF, MMP, and prostaglandin-endoperoxide synthase 2, IL-6, and TGF-β from macrophages.136 The immunosuppression in TME is further driven by a positive feedback mechanism promoted by GM-CSF secreted by carcinoma, resulting in elevated expression‎ of β2-ARs on MDSCs. Following that, β2-AR signaling inhibits glycolysis as well as promotes lipids oxidation, augmenting the immunosuppressive response of MDSCs that is dependent on fatty acid oxidation and carnitine palmitoyltransferase 1A.26,137 Moreover, MDSCs treated with the nxxonselective β-AR agonist (ISO) exhibit increased expression‎ of ARG1 and PD-L1,138,139 contributing to the suppression of T cell-mediated tumor killing, which can be reversed by the use of a β-AR blocker (propranolol). In vitro experiments show that the immunosuppressive effects of MDSCs treated with ISO on the proliferation of CD8+ and CD4+ T cells are stronger than those of the control MDSCs.138,139 Additionally, β-AR activation inhibits type I and II interferon production, which attenuates cell-mediated immune activities against cancer cells as well as oncogenic viruses.140

Adrenergic signaling directly influences tumor cells and concurrently facilitates immune evasion. After exposure to NE in pancreatic cancer cells, there is a significant reduction of MHC I and co-stimulatory ligand B7-1, while the increase of immunosuppressive indoleamine-2,3-dioxygenase and B7H-1, which prompts cancer cells to evade recognition by T cells.141 In mice with B cell lymphoma, AR activation in hematopoietic cells through ISO leads to cancer growth142 which inhibits the proliferation of CD8+ T cells, the production of IFN-γ, and the apoptosis of cancer cells, weakens the reaction of CD8+ T cells to anti-PD-1 and anti-4-1BB therapy, resulting in a significant reduction in tumor-free survival rates.

To study how adrenergic signaling affects CD8+ T cells in cancer, HPV-expressing cancer cells were treated with the STxBE7 vaccine and IFN-α to boost CD8+ T cell reactions. Propranolol elevated the CD8+ T cell infiltration in TME, but did not enhance their reactivity to tumor cells despite raising activation markers and granzyme B production post-vaccination. However, in tumor-draining lymph nodes, naive CD8+ T cells with higher β2-AR expression‎ responded better to β-blockers than the tumor-infiltrating subset, which had reduced β2-AR (Fig. 4). This suggests that using β-blockers early in T cell activation may improve cancer immunotherapy outcomes.142

Clinical trials with metastatic melanoma patients have shown that adding a nxxonselective β-AR blocker to immunotherapy improved survival rates.143 Mouse melanoma models suggest that a selective β-AR blocker targeting β2-AR with anti-PD-1 and IL-2 can optimize response and survival rates. Similar benefits were seen in fibrosarcoma and colorectal cancer (CRC) mouse studies with propranolol, which increased T cell infiltration and reduced MDSCs, boosting antitumor immunity, and its effects were amplified when combined with anti-CTLA-4 treatment.144

Parasympathetic nerve

Acetylcholine (Ach) is the most common neurotransmitter released by parasympathetic nerves. Muscarinic ACh receptors (mAchRs) participate in the cholinergic regulation of the immune system.145 Activation of mAchRs on T cells elevated the levels of aldehyde dehydrogenase in colon antigen-presenting cells in humans and mice,145 which activated Tregs to infiltrate into surrounding tissues. After bilateral subdiaphragmatic vagotomy in mice, the proliferation and invasion of pancreatic ductal adenocarcinoma (PDAC) were promoted, revealing the potential antitumor capability of the vagus nerve.146 Tumor growth was inhibited by treatment with bethanechol (a muscarinic agonist and a parasympathomimetic drug) through mAchR-dependent signaling pathways, which was attributed to elevated immune cells infiltration and a large number of CD44+ epithelial cells in the pancreas, However, the tumor-inhibiting responses disappeared after bilateral subdiaphragmatic vagotomy.147 In the control group, Ach induction of tumor-infiltrating mAchR+ macrophages released TNF-α and inhibited tumor growth, while in vagotomized mice, this cholinergic signaling effect was absent147 (Fig. 4).

Acetylcholinesterase (AChE) is a degrading enzyme that modulates Ach concentration within the interstitial spaces of tissues. By modulating the activity of AChE, an indirect activation of cholinergic signaling effects can be accomplished. Human pancreatic cancer cells have been shown to exhibit high levels of AChE expression‎, leading to subsequent investigations on the impact of AChE inhibitors, such as physostigmine and neostigmine, on the pancreatic tumor TME.148 Pancreatic cancer models have shown that application of ACh, as well as physostigmine and galantamine, reduced the activity and invasiveness of cancer cells.101 That was related to the inactivation of pERK signaling in TME, resulting in a decrease in infiltration of TAMs and secretion of immunosuppressive cytokines.148,149 Nevertheless, in a novel genetically engineered, surgically resectable pancreatic cancer mouse model, no correlation has been found between the concurrent use of AChE inhibitors and overall survival rates.148 Consistently, no difference in survival rates was observed between patients with high AChE levels and those with low AChE levels in pancreatic cancer. Interestingly, in advanced cancer cells, there is a decreased intensity of choline acetyltransferase (ChAT), the key enzyme for ACh synthesis.148

Furthermore, vagal nerve cholinergic signaling is able to promote Trefoil Factor 2 (TFF2) release from memory T cells (Tms) in the spleen, that inhibits inflammation and the development of CRC150 (Fig. 4). In a colitis model, TFF2 levels decrease as inflammation resolves, with MDSCs peaking in inflamed tissues. Vagotomy in mice reduced splenic TFF2 expression‎, while vagal nerve stimulation upregulated TFF2 mRNA. TFF2 knockout mice developed more colon tumors with higher dysplasia and MDSCs infiltration, lacking CD8+ T cell infiltration. These MDSCs expressed more PD-L1, inhibited IFN-γ synthesis as well as the CD4+ T cell proliferation, and increased expression‎ of IL-17A and IL-1β. CD11b+ Gr-1+ MDSCs play a pivotal role in the inhibition of CTLs within TME. Vagus nerve and TFF2-expressing Tms are suggested to inhibit cancer development and MDSCs infiltration into TME.150 Therapeutic methods proposed include TFF2 overexpression‎, viral vector transfection, and TFF2-expressing bone marrow transplantation.

The studies highlight the urgent need for deeper investigations into direct downstream effects of cholinergic signaling within TME as well as its interaction with the immune system.

Neurotransmitters, neuropeptides, neurotrophic factors, and neurometabolites

CNS is rich in neurons that can secrete neurotransmitters and neuropeptides, including NE, ACh, γ-aminobutyric acid (GABA), serotonin (5-HT), dopamine (DA), and histamine (HA). Found beyond the CNS, these same neurotransmitters and neuropeptides are also detected in peripheral tissues. CGRP, NE, and ACh have been discussed previously and will not be reiterated. In peripheral tissues, GABA, 5-HT, DA, and HA are often secreted by immune cells or neuroendocrine cells, and receptors for them exist on immune cells.151,152

B lymphocytes synthesize and secrete the neurotransmitter GABA, which promotes the differentiation of monocytes into anti-inflammatory macrophages. These macrophages secrete IL-10 and inhibit the cytotoxic function of CD8+ T cells.151 Additionally, researchers have found that GABA can bind to GABAA receptors on CD8+ T lymphocytes, suppressing antitumor immunity and promoting tumor growth.151 In non-small cell lung cancer (NSCLC) and CRC, aberrantly expressed glutamate decarboxylase 1 reprograms glutamine metabolism for GABA synthesis. A study of patient specimens shows that elevated GABA levels correlate with a low survival rate. GABA activates GABAB receptors, inhibiting the activity of glycogen synthase kinase 3β, which leads to the enhancement of the β-catenin signaling pathway. This GABA-mediated activation of β-catenin not only promotes tumor cell proliferation but also suppresses the infiltration of CD8+ T cells in the tumor.152

5-HT is commonly secreted by platelets. An interesting phenomenon shows that fluoxetine, a selective 5-HT reuptake inhibitor, has slowed the growth of melanoma by modulating the immune system. It has been found that fluoxetine inhibited the progression of melanoma by inducing T cells to proliferate through mitogen signals. In pancreatic and gastric cancer models, 5-HT has been shown to upregulate the expression‎ of PD-L1 through histone serotonylation and subsequent epigenetic regulation of immune checkpoint expression‎.153 Additionally, the precursor of 5-HT, tryptophan, is metabolized by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) into kynurenine, which is involved in neuroactivity and immune modulation and is associated with neurodegenerative diseases and cancer.153

Recent studies highlight the link between the DA system and cancer. DA influences tumor behavior via its receptors, categorized as D1-like (DRD1, DRD5) and D2-like (DRD2, DRD3, DRD4), which vary in tumor expression‎ and function. DRD3 expression‎ is linked to liver cancer prognosis; lower levels correlate with worse survival outcomes. DRD3 agonists reduce HCC cell proliferation and invasion, while antagonists have the reverse effect.154 DA via DRD5 promotes CD8+ T cell differentiation into CD103+ tissue-resident Tms, enhancing the antitumor immune response. In CRC, higher DA levels are linked to better patient survival and increased CD8+ T cell infiltration.155 DA transporter antagonists like vanoxerine are being explored for cancer treatment, vanoxerine inhibits colorectal cancer stem cells (CSCs) function by downregulation of G9a histone methyltransferase and activates endogenous transposable elements and type I interferon responses to enhance tumor lymphocytic infiltration, offering a new strategy to boost the antitumor immune response.156 In the co-culture system of glioma stem-like cells (GSCs) spheres with brain organoids, the DRD1 inhibitor, SKF83566, suppressed GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interaction. The ability that SKF83566 can cross the blood–brain barrier makes it a promising small-molecule drug for GBM.157

Elevated HA levels are found in cancer patients’ blood and tumors, likely due to increased L-histidine decarboxylase (HDC) in cancer cells. The role of HA and its receptors in tumors is debated, but HA is known to influence the TIME.158 Cimetidine, an H2 antagonist, inhibits lung tumor growth in mice by reducing CD11b+ Gr-1+ MDSCs.159 Increased HA and H1 receptors in the TIME can promote an immunosuppressive M2-like macrophage phenotype, which regulates the immune checkpoint VISTA to inhibit T cells. H1 antagonists can counteract this, enhancing responses to PD-1 monotherapy in patients on antiallergic drugs.160 The H4 receptor, expressed in immune cells including T cells, is a potential target for treating inflammation and autoimmune diseases. Activation of the H4 receptor can influence T cell function, either directly or indirectly, by affecting other immune cell subsets. In a breast cancer model, the absence of the H4 receptor correlated with slowed tumor growth and improved survival rates.161

In HNSCC, GDNF, a neurotrophic factor secreted by nerves, can enhance the expression‎ of PD-L1 on tumor cells by activating the JAK2-STAT1 signaling pathway. The interaction between PD-L1 and PD-1 on T cells aids tumor cells in evading immune surveillance and attack.162

A recent study has discovered that CNS-enriched metabolite N-acetylaspartate is highly expressed in breast cancer cells. It disrupts the formation of the immunological synapse by promoting the P300/CBP-associated factor (PCAF)-induced acetylation of laminA-K542, thereby inhibiting the cytotoxicity of NK cells and CD8+ T cells, ultimately impairing antitumor immunity.163

Neurotransmitters, neuropeptides, neurotrophic factors, and neurometabolites can exert diverse influences on tumorigenesis and tumor progression. Investigating their specific roles in various cancers could facilitate the modulation of these pathways to complement antitumor therapies. Through elucidating the mechanisms by which each neurotransmitter interacts within the TME, thereby influencing cancer cell behavior, precision therapies could be engineered to optimize these interactions, potentially augmenting the efficacy of oncology treatment strategies. This strategy may offer enhanced refinement and individualized approaches to cancer therapy, leveraging a triangular relationship between neurons, immune cells, and cancer cells.

Glial cells

Within the oncological milieu, glial cells constitute a significant component of the neuro-immune axis. Within the peripheral nervous system, the myelin sheath, predominantly formed by Schwann cells, plays a crucial role in the reparative processes of axonal integrity.164 Furthermore, these Schwann cells augment the chemotactic migration of immune cells through the secretion of chemotactic cytokines. Activated glial fibrillary acidic protein (GFAP+) Schwann cells, when co-cultured with melanoma-conditioned medium, upregulated expression‎ of genes participating in immune surveillance and chemotaxis, such as IL-6, TGF-β, and VEGF.165 It has been shown that CCL2, synthesized and secreted by Schwann cells, promoted proliferation in co-culture experiments with HeLa and ME180 cervical cancer cells.166 The modulation of the TIME by CCL2 is associated with immune suppression, which is related to poor overall survival rates in human melanoma.167 After the secretion of CCL2 into the TME, TAMs polarize into the M2-type, promoting tumorigenesis and suppressing antitumor immune responses.167 In addition, Schwann cells also modulate the recruitment of suppressive MDSCs and enhance the growth of melanoma, pancreatic, and prostate cancers.167,168,169

Furthermore, previous studies have indicated that Schwann cells possess Toll-like receptors (TLRs) and can recognize damage-associated molecular patterns (DAMPs), especially in diseases involving nerve damage.169,170 DAMPs are produced by various cancers, including pancreatic cancer, breast cancer, CRC, and GBM, that are detected by TLRs on macrophages and DCs within TME.171 It is proposed that TLRs expressed on Schwann cells may play a role in the immune response within the TME by recognizing DAMPs secreted by the tumor. Upon TLR activation, innate immune responses are promoted, including the maturation of antigen-presenting cells and subsequent T cell activation.172 Additionally, Schwann cells express CD74, CD1a, CD1b, CD1d, B7-1, BB-1 and cell adhesion molecule CD58, supporting their role as antigen-presenting cells. Further investigations are needed to elucidate the function of these molecules within the TME.173,174,175

The interaction between peripheral neuroendocrine cells and immune cells

Neuroendocrine cells originate from the neural crest cells of the neural ectoderm and the endoderm cells encoded by the neuroepithelium. They are epithelial cells with many characteristics of neuronal cells, including numerous secretory vesicles and the ability to sense environmental stimuli.176 Upon sensing danger, neuroendocrine cells can communicate with nerve terminals, triggering neural reflexes that protect the body from harm.177 Peripheral neuroendocrine cells are distributed throughout various systems in the body, such as the respiratory tract, gastrointestinal tract, prostate, pancreas, and so on.119,178,179

Neuroendocrine cells can interact with immune cells to regulate inflammatory responses within the body. For instance, neuroendocrine cells in the respiratory tract can interact with eosinophils through CGRP and extracellular traps, exacerbating asthma.119 In the gut, IL-33 can be sensed by enterochromaffin cells, leading to the release of 5-HT. This release, upon activation of intestinal neurons, promotes intestinal motility. Mechanistically, IL-33 triggers an influx of calcium ions through an atypical signaling pathway, inducing the secretion of 5-HT, which emphasizes the significant role of the IL-33-ST2 signaling pathway in regulating intestinal motility and host defense. The findings reveal an immuno-neuroendocrine axis that rapidly modulates the release of 5-HT to maintain intestinal homeostasis.178

Unregulated proliferation of neuroendocrine cells can lead to the development of neuroendocrine cancers, such as small cell lung cancer (SCLC)180 and gastrointestinal neuroendocrine cancers (GEP-NENs).181 It has been found that SCLC tumors possess an immunosuppressive landscape, compared to normal adjacent tissues (NATs), tumor tissues exhibit greater lymphocytic infiltration and less myeloid cell infiltration. This suggests that adaptive immunity plays a more significant role in TME, while innate immune responses are more crucial in normal lung tissue. T cells from both NATs and TME are primarily composed of CD8+ T cells and express high levels of cytotoxicity markers such as GZMA/B/H/K, PRF1, NKG7, IFNG, GNLY, and CXCL13, indicating significant immune surveillance in SCLC.180 Compared to cytotoxic T cells from NATs alone, T cells from the TME display increased diversity, including four states of heterogeneous activation based on naive, cytotoxic, exhausted, and proliferative characteristics. Detailed classification of T cells in SCLC also reveals the expression‎ patterns of dysfunction and exhaustion markers (such as PD-1, CTLA-4, TIM3, LAG3, TIGIT, and LAYN), which may serve as targets for immunotherapy.180 In the field of digestive system neuroendocrine tumors, different regions of GEP-NENs exhibit distinct TIME characteristics. For instance, pancreatic neuroendocrine tumors (Pan-NENs) differ from small intestine neuroendocrine tumors (SINENs) in terms of T cell infiltration and PD-L1 expression‎.182 Studies have shown that both tumor and non-tumor areas in Pan-NENs have a high level of T cell infiltration, including CD3+, CD45RO+ (Tms), and CD8+ T cells. Compared to SINENs, Pan-NENs exhibit more T cell subset infiltration in non-tumor areas, suggesting a more active immune response in Pan-NENs. PD-L1 expression‎ is quite common in Pan-NENs, approximately 97%, which may be related to the tumor’s immune evasion mechanisms. In contrast, PD-L1 expression‎ in SINENs is not widespread, which could affect the efficacy of immunotherapy and the TIME.182

The presence of neuroendocrine differentiation in tumors may indicate a poor prognosis. For instance, in prostate cancer, patients with neuroendocrine cell positive staining assessed by objective criteria have been shown to have worse outcomes in terms of biochemical progression and prostate cancer-specific survival, even among patients with low-risk cancer.179 This finding suggests that future studies should establish the precise quantitative thresholds for reporting neuroendocrine cell staining to more accurately identify patients at higher risk of progression. This could help improve clinical management strategies.179

The impact of circadian rhythms on tumor immunity

The circadian rhythm is an internal timekeeping mechanism controlled by the neural system within living organisms that regulates many physiological and behavioral responses, including the sleep-wake, feeding-fasting, and activity-rest cycles. The circadian clock system comprises central and peripheral clocks.183 The central clock, located in SCN, operates autonomously and coordinates peripheral clocks throughout the body by sending signals.184 In rats, the diurnal expression‎ of vasoactive intestinal peptide (VIP) in SCN is influenced by the light/dark cycle, and VIP plays a significant role in the regulation of circadian rhythms and immune responses.185 Furthermore, the cholecystokinin (CCK) neurons in the SCN are instrumental in maintaining the robustness of the circadian rhythm. Notably, across diverse photoperiods, a surge in the calcium activity of CCK neurons is observed just before the commencement of mice’s nocturnal activity, suggesting their role in heralding the onset of nighttime behavior. These CCK neurons engage in a negative feedback mechanism with VIP neurons, effectively dampening the activity of the latter. This interaction is crucial as it mitigates the desynchronizing effects of light exposure on the SCN, thus preserving the stability of rhythmic behavior, particularly during extended photoperiods.186 The SCN regulates the diurnal fluctuations of immune cell traffic in peripheral lymph nodes through the autonomic nervous system.185,187 Cortisol and adrenaline can control the opposite diurnal rhythms of T cell subsets, with these hormones modulating immune responses through various signaling pathways.188 Adrenergic innervation governs the diurnal recruitment of leukocytes into tissues.189 Sleep deprivation or irregular sleep patterns may lead to a decline in immune function, thereby weakening the body’s immune surveillance and clearance capabilities against tumors.190 On the other hand, physiological activities and psychological stress during the waking state may affect the function of immune cells through neuroendocrine pathways, thereby affecting tumor immunity191 (Fig. 5).

Fig. 5

The impact of circadian rhythms on tumor immunity. The circadian clock system is composed of central and peripheral clocks. The central clock, located in the SCN of the anterior hypothalamus, operates autonomously and coordinates peripheral clocks throughout the body by sending signals. SCN, which are located immediately above the optic chiasm in the anterior-ventral area of the hypothalamus, are believed to include the pacemaker of this clock. This circadian clock reset comes about through the retinohypothalamic tract, which sends light information directly from the retina to a subset of SCN neurons. A pineal hormone known as melatonin is most abundant in the blood at night and least preval‎ent during the day. Its secretion is governed by a rhythm-generating process in the SCN, which is regulated by light. Melatonin is not only regulated by the circadian oscillator but also provides the oscillator with a feedback signal for darkness. Bilateral structure of the SCN and its “core” and “shell” subregions with VIP and gastrin-releasing peptide (GRP) in the light-responsive core and arginine vasopressin (AVP)-expressing cells in the shell, the diurnal expression‎ of VIP in the suprachiasmatic nucleus is influenced by the light/dark cycle, and VIP is involved in the regulation of circadian rhythms and immune responses. The CCK neurons exhibit photic antagonism and can form a negative feedback loop with VIP neurons, inhibiting the activity of VIP neurons. At the molecular level, the circadian rhythms from both the central and peripheral clocks are similar. BMAL1 in macrophages inhibits the production of HIF1α and reactive oxygen species (ROS), inhibiting the polarization of macrophages to the M2-type, which enhances the activation of CD8+ T cells and suppresses tumor growth. RORγ enhances the differentiation and effector functions of Th17 cells. RORγ reduces the levels of Tregs. The activation of RORα can enhance the activity and function of CD8+ T cells by alleviating the NF-κB pathway. BMAL1 in B cells and neutrophils can change their migration ability via modulating the expression‎ of promigratory molecules that may affect tumor growth. optic chiasm (OC); the 3rd cerebral ventricle (V3). This figure was created with BioRender (https://biorender.com/)

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At the molecular level, the circadian rhythms from both the central and peripheral clocks are similar and are controlled by clock genes. Clock genes are a class of genes within organisms that regulate circadian rhythms.185 The proteins encoded by these genes form intricate regulatory networks to sustain biological rhythms. The central molecular clock mechanism is regulated by transcription-translation feedback loops (TTFL).192,193,194 Brain and muscle ARNT-like protein 1 (BMAL1) and Circadian locomotor output cycles kaput (CLOCK) form part of positive feedback loop, which bind to E-box motifs as well as elevate transcriptional repressors, such as the cryptochrome (CRY1 and CRY2) and period (PER1, PER2, and PER3) genes. CRY and PER form a complex that enters the nucleus and inhibits the CLOCK-BMAL1 complex.195,196,197 Additionally, the CLOCK-BMAL1 complex modulates the level of nuclear receptors REV-ERBα/β198 as well as Retinoid X receptor-related orphan receptors (RORs), which inhibit or activate BMAL1, forming a second feedback loop.191,192,193,199,200 SCN neurons maintain synchronization through synaptic connections, couple with each other, and transmit signals to peripheral clocks via neural and neuroendocrine stimulation, achieving a coherent rhythm throughout the organism.185

Circadian disruption and cancer

Circadian disruption is implicated in the pathogenesis of various diseases, including tumor.201,202,203 There is a growing body of evidence suggesting that circadian disruptions, such as night shift work and eating late at night after 9:30 PM, known as “night eaters,” increase the risk of cancer204,205,206,207 and are related to heightened tumor metastasis in several cancer types, such as breast cancer,208,209,210 NSCLC,211 HCC212 and CRC.213 The significance of this direction is also supported by studies in mouse models, which demonstrate that the circadian clock plays a crucial role in tumorigenesis and in modulating the efficacy of radiotherapy214,215 and chemotherapy.216,217 Mechanistically, the circadian clock can influence cancer development via regulating various hallmarks of cancer,218,219 including DNA damage, apoptosis, cell cycle and senescence,192,204,220 proliferation,192,210 metabolism,191,219,221 replicative immortality,222 and genomic instability and mutation.223

CSCs are a subpopulation of cancer cells with self-renewal capabilities that significantly promote tumor initiation, metastasis, and therapy resistance.224 Elevating proofs suggest that the circadian clock is crucial for sustaining the stemness of CSCs across diverse sorts of cancer, such as acute myeloid leukemia (AML) and GBM.225,226,227 Particularly, in AML, pharmacological along with genetic disruption of circadian clock mechanism leads to CSC differentiation,227 Furthermore, within GBM, it impairs the stemness of GSCs and leads to GSC cell cycle arrest and apoptosis.225,226 The compound SR8278, which can reduce PER2 expression‎, may protect mice from pituitary adenoma development by restricting cell cycle progression.228 These findings indicate that core components of the circadian clock modulate key biological characteristics of cancer cells across cancer types.

Circadian disruption in the TIME

In addition to the aforementioned effects on cancer cells, circadian disruption also affects TIME.203 In vivo findings from mouse models of breast cancer and melanoma indicate that circadian disruption notably promotes cancer progression, while also inducing a shift toward an anti-inflammatory macrophage phenotype through raising the ratio of TAMs as well as Tregs, and reducing the infiltration and activity of CD8+ T cells.229,230 Similarly, bioinformatics analyses of gene expression‎ data from human cancer tissues have uncovered correlations between clock genes and infiltration of immunocytes and proliferation of cancer cells.179

Clock genes in tumor cells can influence tumorigenesis by modulating the TIME. For instance, in GBM, high levels of CLOCK in GSCs are associated with an increase in microglia in TME, mediated by the transcriptional regulation of chemokine-like protein 3.225 The deficiency of Bmal1 in melanoma cells also impacts immunocytes within TME, including CD8+ T cells and TAMs.231 In kidney clear cell carcinoma (KIRC) and breast cancer, the expression‎ of clock genes (such as CLOCK, BMAL1, and PER3) in cancer cells exhibits rhythmic fluctuations. That is also related to infiltration of macrophages, neutrophils, as well as DCs.220,232 Multi-omics analyses of KIRC and NSCLC show that clock genes (such as CLOCK, BMAL1, CRY1, CRY2, PER1, PER2, PER3, RORA, and REV-ERBα/β) are associated with infiltration of lymphocytes, including B cells, CD8+ and CD4+ T cells.220,233 Similarly, patient-derived GSCs exhibit diurnal oscillations independent of tumor genetics,226 and the expression‎ of CLOCK in GBM is correlated with reduced levels of activated CD8+ T cells.225 Furthermore, genomic mutation analysis show that clock genes often mutate in cancer patients, which in turn can induce genomic instability, correlate with the exhaustion of T cells (such as CD8+ and CD4+ T cells), and are associated with the upregulation of immune suppressive molecules, including PD-L1 and CTLA-4.234,235 In vivo outcomes from both syngeneic or allogeneic leukemia models have shown that the recruitment and implantation of leukemia cells/leukocytes was modulated by circadian clock. While the disruption of the circadian rhythm increased the tumor burden.236 In T cell acute lymphoblastic leukemia, key components of the circadian clock, CLOCK, along with BMAL1, can influence the activity of leukemia-initiating cells through regulating the JAK/STAT axis.200

Clock genes in immune cells can also influence tumorigenesis. When TAMs polarized toward an immunostimulatory phenotype, the expression‎ of BMAL1 in macrophages was elevated. Knockout of BMAL1 in macrophages resulted in the upregulation of HIF1α and accumulation of reactive oxygen species (ROS), as well as a decrease of nuclear factor erythroid 2-related factor 2, thereby modulating the synthesis of pro-inflammatory cytokines.237,238 Consequently, compared to Bmal1 WT mice, mice with bone marrow-specific Bmal1 knockout exhibited increased tumor growth and alternatively activated TAMs.237 Similarly, co-injection of Bmal1 knockout macrophages with cancer cells enhanced cancer growth as well as inhibited CD8+ T lymphocytes infiltration versus WT macrophages.237 Therefore, these emerging evidences emphasize that BMAL1 in macrophages is crucial for inhibiting tumor progression and promoting antitumor immunity (Fig. 5). The activation of REV-ERBα can inhibit CCL2 and its downstream signaling (such as ERK and p38 MAPK), thereby suppressing the adhesion and migration of macrophages.239 Transcription factor, RORγt, is an intracellular clock component that controls the differentiation of CD4+ Th17 cells, which produce IL-17, depending on the circadian clock.240 Activation of RORγ with synthetic agonists can enhance the differentiation and effector functions of Th17 cells and reduce Tregs through modulating cytokines/chemokines, co-stimulatory receptors, as well as immune checkpoint molecules.241 Thus, co-culture and co-injection of CD8+ Tc17 cells and EG7 lymphoma cells treated with RORγ agonists increased apoptosis in vitro and inhibited tumor growth in vivo.241 Furthermore, studies in mouse models of breast cancer and CRC showed that RORγ signaling prevented cancer development as well as prolonged the survival of the animal hosts by promoting antitumor immune responses.241 It is noteworthy that the impact of RORγ activation on Tregs may not be attributed to its circadian clock, as Tregs lack intrinsic circadian oscillators.242 Besides RORγ, the activation of RORα can enhance the activity and function of CD8+ T cells via alleviating the NF-κB pathway as well as maintaining the balance of cholesterol metabolism in CD8+ T cells. Eventually, these activated CD8+ T cells induce apoptosis in CRC cells243 (Fig. 5). In conclusion, the studies demonstrate that specifically targeting RORs of T cells will be a potential approach for immunotherapy. The particular deletion of Bmal1 in B cells, neutrophils, or endothelial cells in mice can eliminate the diurnal variation in the expression‎ of promigratory molecules, including integrin αL (CD11a), P-selectin glycoprotein ligand 1 (PSGL-1), intercellular adhesion molecule 1, or vascular cell adhesion molecule 1, thereby eliminating the rhythmic homing of B cells and neutrophils185 (Fig. 5). DCs exhibit a rhythmic migration to the tumor-draining lymph nodes in a manner that is dependent on the diurnal expression‎ of the co-stimulatory molecule CD80, which in turn governs the circadian rhythmic response of tumor antigen-specific CD8+ T cells.244 However, the researchers did not further investigate the correlation between the circadian expression‎ of CD80 and clock genes, which warrants further investigation.

The overexpression‎ of CRY1 in endothelial cells can inhibit the activation of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, adhesion molecules (such as VCAM-1, ICAM-1, and E-selectin), and the NF-κB pathway, all of which impair the adhesion of monocytes.245,246

In addition to the previously discussed cell types in the TME, the complement system must also be considered. It is closely related to the circadian clock247 and plays a key role in enhancing tumor progression by promoting MDSCs infiltration and restricting CD8+ T cell-mediated immune responses.248

Although an elevating number of studies focus on the role of clock genes in TME, there is a paucity of research on how the CNS and central clock regulate peripheral clocks. Additionally, there is a lack of research on how alterations of clock genes in the TME impact central rhythms. Further studies are warranted to elucidate the complete circuitry between rhythms within TME and central rhythms.

T cell-targeted immunotherapies and the role of circadian regulation

Current immunotherapies targeting T cells include immune checkpoint inhibitors (ICIs) and CAR-T cell therapy.249 Considering the significant role of the circadian clock in modulating interactions between cancer cells and TME to influence T cell function, as previously highlighted, a deeper comprehension of this interplay could potentially result in approaches that enhance the efficiency of immunotherapy.250 Preclinical studies in mice have shown that the use of RORγ agonists can promote the antitumor immunity of CAR-expressing Th17 cells, providing long-term protection against tumors.251 Furthermore, the crosstalk between cancer cells and the TME, regulated by circadian clock components, is associated with an increased infiltration of MDSCs, which consequently impairs T lymphocyte functions and upregulates immune checkpoint molecules.220,225,232,233,235,252 These studies indicate that targeting the TME-cancer cell crosstalk regulated by circadian clock components may enhance the antitumor efficiency of ICIs. In fact, this concept is supported by clinical proof, where the antitumor effects of nivolumab (an anti-PD-1 antibody) in patients with advanced pulmonary cancer were notably higher in the morning treatment group compared to the afternoon treatment group.253 Since CD8+ T cells exhibit rhythmic oscillations within TME, adjusting the timing of CAR-T cell therapy or ICI treatments according to this rhythm could improve efficacy.246,254,255,256,257 Similarly, scheduling radiotherapy and chemotherapy according to a patient’s circadian rhythm may enhance treatment effectiveness and reduce side effects.258 Additionally, a clinical trial testing the combination of RORγ agonists with anti-PD-1 antibodies for patients with metastatic NSCLC is underway (NCT03396497).

These findings indicate that the circadian clock may influence the clinical response to ICI treatment and CAR-T cell therapy. Further investigations focused on understanding the interactions between cancer cells and the immune system, as regulated by circadian clock components, will aid in the design and development of novel, effective, circadian clock-oriented immunotherapies.

The impact of stress on tumor immunity

Stress is the physical and emotional response experienced by individuals when encountering life’s challenges and is governed by the nervous system. Chronic stress activates the sympathetic nervous system and the HPA axis, resulting in elevated release of catecholamines (CAs) and GCs.259,260 These are referred to as stress-associated immunomodulatory molecules which exhibit immunosuppressive or immunostimulatory functions based on the cells targeted, stressors intensity, sustained period, as well as interaction with immune reaction.261,262,263 Despite the widespread expression‎ of GC receptors (GRs), the immunomodulatory effects of GCs are highly cell type-specific264,265 depend on different transcriptional outputs and post-translational modifications (PTMs) of the receptors266 (Fig. 6). Dopamine metabolism, transmission, conversion, neuronal innervation, and release are all affected by stress,267,268,269 that promotes primary CD8+ T cells homing,270 restricts NK cells and the production of IFN-γ,271 and mitigates the activation of the NLRP3 inflammasome272 through interacting with different dopamine receptors. A surge in NE during acute stress can rapidly enhance the antigen capture of DCs through α2-AR-triggered PI3K and ERK1/2 signaling pathways.273 However, stimulating β2-AR on DCs results in the priority release of IL-23, thereby enhancing Th17 response and reducing the Th1 response in CD4+ T cells.274 β2-AR signaling activation by NE is able to magnify the inhibitory capacity of Tregs through the overexpression‎ of CTLA-4.275 Chemogenetic activation of the sympathetic nervous system or administration of AR agonists can imitate stress states within murine models that cause vascular constriction, lessen blood supply locally, as well as trigger rapid oxygen deprivation, impairing T cell movement and defense mechanisms.44 The above studies suggest that the characterization and density of the receptors specific to diverse immunocytes determine neuroendocrine modulation of immune responses.276,277 This intricate interplay between the stress response and the immune system highlights the complex regulatory network that can influence immune function and has implications for understanding the role of stress in immune-related diseases, including cancer.

Fig. 6

The impact of stress on tumor immunity. Stress activates the HPA axis and sympathetic nerves, resulting in elevated GCs and CAs in the blood and TME, which can engage GR, GPR97, and CA receptors on immune cells. This leads to transcriptional reprogramming, modified signal transduction, and functional alterations. TAM-mediated clearance of tumor cells is disturbed by repression of Lrp1 and the elevation of Sirpa. GCs can also drive TAMs toward an M2-like phenotype and inhibit the expression‎ of genes Tnf, Il1b, and Il-6. GCs dampen the cytolytic activity of NK cells by reducing histone acetylation of genes Prf, Gzmb, and Ifng. They also limit the production of IFN-γ by upregulating the gene Pdcd1. GR signaling enhances MDSC immunosuppression by repressing Hif1α, Glut1, Eno1, Mct4, Tnf, and Il1b. GCs confer immunosuppressive properties on DC by downregulating genes Cd80, Cd86, Il-12, Il-6, and Tnf, while augmenting the expression‎ of genes Il-10. The transcription of Tsc22d3 is elevated in DC, which impairs type I interferon responses and MHC class I/II antigen presentation pathways, thus compromising antitumor immunity. GC-induced downregulation of anti-apoptotic molecules leads to apoptosis of DCs. By stimulating the expression‎ of Bim, Bak1, and Bax in T cells, GCs can activate the mitochondrial pathway of T cell apoptosis. They also dampen the function of T cells by upregulating genes Tsc22d3, Dusp1, Nfkbia, Pdcd1, Ctla-4, and Lag3, while downregulating Prf, Gzmb, and Ifng. They can drive various transcriptomic and epigenetic changes that favor the differentiation of Tregs, whereas strongly restraining memory precursor T cells, CTLs, and Th1 cells differentiation via upregulation of Tcf1. GCs block the accumulation of neutrophils in inflamed tissues by downregulating Sell and upregulating Anxa1. Moreover, GCs exhibit an anti-apoptotic effect on neutrophils by directly activating p38 MAPK and PI3K and upregulating genes Mcl1 and Xiap. They control the expression‎ of key clock genes (Per1 and Per2), leading to an abnormal “aged” phenotype in neutrophils and the formation of NETs, which promote the migration of cancer. Activation of β-ARs in CTLs leads to upregulation of Nr4a1, resulting in T cell dysfunction. CAs also promote tumor infiltration and M2 polarization of TAMs, thus accelerating the progression and metastasis of cancer. Upon stimulation with NE, neutrophils rapidly release S100A8/A9 and activate myeloperoxidase to generate oxidized lipids, which further reactivate dormant tumor cells. β2-AR activation can facilitate the conversion of naive T cells to Treg cells and enhance their suppressive activities by increasing CTLA-4 expression‎. β2-AR signaling in MDSCs leads to downregulation of apoptosis-related genes and upregulation of Arg1 and Cd274. The β2-AR axis also promotes tumor progression via the CXCL5–CXCR2 axis and MMPs, which enhance the mobilization of MDSCs and local immunosuppression. This figure was created with BioRender (https://biorender.com/)

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Stress has been shown to regulate tumor immune surveillance, with increased UV-induced squamous cell carcinoma sensitivity in restrained mice linked to elevated Tregs and reduced IFN-γ production by T cells.278 High stress levels also correlate with impaired NK cell function in ovarian and breast cancer patients.22 Understanding the TME’s immune dynamics and their stress-induced molecule alterations is vital for enhancing immunotherapy effectiveness. The neuroendocrine-immune system interplay significantly shapes the antitumor immune response, offering new therapeutic avenues.

GCs

Synthetic GCs exhibit strong anti-inflammatory and immunosuppressive effects at pharmacological doses. However, stress-induced elevations in endogenous GCs can either suppress or enhance immune responses, depending on factors such as dosage, timing, duration, target cells, and associated transcriptional changes.279 During acute stress, the PVN uses GC signaling to control leukocyte migration, while exercise circuits mobilize neutrophils to injury sites, indicating brain regulation of leukocyte distribution and function.280 In rodents with tumors, stress from surgery or environmental factors can reduce the effectiveness of immunotherapy, while blocking GC and ARs can enhance NK cell activity and survival.281 Repeated social defeat stress in mice impairs the efficacy of chemotherapy, cancer vaccines, and ICIs.282 This stress preconditioning elevates GCs, reducing NE and 5-HT levels, and impairs DC function,283,284 inducing T cell impairment along with therapeutic inefficacy.282 The efficiency of chemotherapeutic interventions or vaccines can be negated by clinical doses of synthetic GCs or overexpression‎ of TSC22 domain family member 3 (Tsc22d3) in DCs of unstressed mice, but using a GC receptor antagonist or deleting Tsc22d3 can counteract stress-induced immunosuppression.282 Mifepristone has shown benefits in reducing tumor progression and improving life quality for patients suffering from various tumor types.285,286,287 GCs inhibit neutrophil aggregation within areas of inflammation by decreasing Sell and increasing Anxa1. In addition, they can activate p38 MAPK and PI3K, increase Mcl1 and Xiap gene expression‎, as well as block neutrophil apoptosis.288,289,290 In a breast cancer model, GCs alter neutrophil circadian rhythms, promoting NET formation and tumor metastasis291 (Fig. 6). Emotional stress in patients with advanced NSCLC treated with ICIs is associated with poorer outcomes, suggesting the importance of addressing emotional stress in cancer management, as it can activate the HPA axis and increase GCs release, potentially affecting ICI effectiveness.292,293 The concept of “psycho-biomarker” has been proposed for potential application in various cancers.

GCs are produced by monocyte-macrophage lineage cells in TIME as well. These locally produced GCs can bind to GR and upregulate the transcription factor TCF1, leading to the dysfunction of CD8+ T cells. This in situ GC secretion is related to the failure of immunotherapy in preclinical models of melanoma and in patients with melanoma.261 In NSCLC patients, scRNA-seq has indicated an association between the expression‎ of TSC22D3 in tumor-infiltrating DCs and peripheral blood monocytes. Additionally, the studies revealed a positive association between circulating levels of cortisol and the levels of TSC22D3 in monocytes of the peripheral blood and the emotional state of patients with CRC or NSCLC.282,294 In a variety of cancers, a high level of TSC22D3 is considered an indicator of poor prognosis.282 Indeed, NSCLC patients treated with corticosteroids show a poorer response to PD-1/PD-L1 blockade.295 It is currently unclear whether this is due to the immunosuppressive effects mediated by corticosteroids or simply because advanced cancer patients are more susceptible to get a large amount of corticosteroids for palliative therapy. Though GCs can impair immune regulation of tumors, they are not likely to impact the potency of PD-1 treatment of mouse models with intracranial glioma, possibly due to the unique immunoprivileged TME.296 In a mouse model of mesothelioma, dexamethasone was discovered to facilitate lymphocyte depletion within the bloodstream, except for TIME that could elucidate its substantial adverse effect on the advantages of weak chemotherapy combined with immunotherapy.297 However, GC treatment did not significantly inhibit the therapeutic effects in mice with mesothelioma undergoing effective cancer treatment.297 Thus, the impact of GCs on tumor immunosurveillance and therapeutic efficacy depends on their accessibility within TME, the anatomical location of the tumor, and the immunogenicity of the cancer therapy.

CAs

CAs, such as DA, have a complex role in the immune system and are generally considered immunosuppressive factors.272,298 However, they can also stimulate the immune system under certain conditions.299,300 Aversive stimuli can enhance the release of DA within the mesolimbic system of mice and humans,268,301 while chronic psychosocial stress can suppress dopaminergic activity.302 Notably raised DA concentrations of blood reflect the stress responses associated with malignancy progression. For lung cancer, the increase of circulating DA effectively prevents T cell expansion and toxicity through DRD1.303 In mouse models with melanoma, DA has been demonstrated to be immune-suppressing as well. Cross-presentation of tumor antigens by DCs and effector T cell responses can be enhanced by inhibition of DRD3.304 However, DA signaling is beneficial for antitumor immunity in some cases. Such as, in mouse models of lung cancer, the activation of DRD2 on MDSCs reduces their tumor infiltration.305 Moreover, DA targeting DRD1 reduced nitric oxide production of MDSCs, subsequently reversed local immune suppression of mice with NSCLC and melanoma.306 These findings highlight the dualistic nature of CAs in modulating immune responses and suggest that their effects may depend on the context, the specific receptors involved, and the type of immune cells they interact with. Understanding these intricate relationships is essential to creating effective strategies to modulate immune response in cancer treatment.

The immunosuppressive effects of adrenergic signaling in lymphocytes are widely reported. It rapidly and efficiently increased the expression‎ of the orphan nuclear receptor subfamily NR4A, a key mediator of T cell dysfunction.307,308 NR4A1 increase inhibited gene expression‎ for some effector proteins, and knockout of Nr4a1 within mice enhanced the antitumor immunity.309 CAs are highly effective in suppressing the initiation of antitumor CD8+ T cell responses, which may be attributed to the relatively high expression‎ of β2-ARs in naive T cells.310 In a mouse model of B cell lymphoma, long-term use of ISO largely eliminated the efficacy of tumor vaccines targeting NKT cells and immunotherapies targeting co-stimulatory or coinhibitory molecules. This is primarily as a result of the decline in cytotoxic T cell activities.142 Advanced study indicates that prolonged adrenal signaling activation of CD8+ T cells inhibited metabolic adaptation, resulting in damaged mitochondrion and affecting glucose metabolism.311 In addition, a significant increase in CAs caused by stress favored myeloid cell-driven immunosuppression. β2-AR signaling has been shown to enhance the M2-type macrophage activation in mammary cancer, which subsequently accelerates their infiltration in the tumor and promotes metastasis.140,312 This signaling additionally contributed to the accumulation of MDSCs in TIME and increased Arg1 and PD-L1 levels.138 In individuals with prostate tumors, particularly those with depression manifestations, NE-induced neuropeptide Y has been shown to be related to a higher intensity of CD68+ TAMs, which inhibited antitumor immunity locally.313 These findings underscore the complex interplay between the nervous system, the immune system, and cancer progression, highlighting potential targets for intervention to enhance the efficacy of cancer immunotherapies.

The genetic deletion or pharmacological inhibition of β2-ARs, using agents such as ICI118.551 or propranolol, rather than blocking β1-ARs with metoprolol,143 has been shown to enhance the efficacy of targeted-PD-1 treatment of mice with melanoma and mammary cancer.314,315 Similarly, the blockade of stress-induced β2-ARs significantly improved the abscopal effect of ionizing radiation therapy in mice with melanoma, breast cancer, and CRC, by boosting antitumor immunity.316 The combination of β2-AR inhibition and local injection of TLR2 agonists has been shown to amplify the efficiency of tumor antigen-loaded DC vaccines in mice with thymoma.317 It has been supported that pharmacologic inhibition of β-AR improved antitumor immunity of cancer patients in clinical trials recently. In a study involving participants with breast cancer, preoperative application of nxxonselective β-AR antagonist propranolol decreased intratumoral mesenchymal polarization, promoted M1-type macrophages along with conventional type DCs infiltration in TME, as well as enhanced the aggregation of CTLs within the tumor318 (Fig. 6). In another randomized, placebo-controlled phase II clinical trial, the perioperative inhibition of β-ARs and cyclooxygenase-2 (COX-2) in breast cancer patients significantly suppressed the expression‎ of genes related to epithelial-mesenchymal transition. It also decreased the activation of transcriptional regulators that promote metastasis or inflammation.319 This combined therapy also enhanced the production of IL-12, IFN-γ and CD11a, inhibited the secretion of IL-6 and C-reactive protein, and reduced the mobilization of CD16− monocytes.319 These findings suggest that targeting the adrenergic signaling pathway may be a promising strategy to improve the effectiveness of cancer immunotherapies and that the timing and combination of such interventions could be critical in optimizing treatment outcomes.

In a non-randomized, non-blinded clinical trial, non-indicated administration of propranolol upon cancer diagnosis was found to reduce the chance of relapse for melanoma.320 In another study, metastatic melanoma participants using nxxonselective β-AR inhibitors, instead of selective β1-AR antagonists, had an extended overall survival period after receiving therapy targeted with IL-2 plus CTLA-4 and/or PD-1 checkpoint inhibitors.321 The β-AR antagonist deserves to be investigated further, enabling it to be used more precisely in specific TME. Interestingly, the activation of dopaminergic input from the ventral tegmental area to the medial prefrontal cortex using optogenetic methods was found to alleviate anxiety symptoms induced by chronic stress, reverse the increase in cytokines associated with tumor growth and progression (such as VEGF, bFGF, and IL-6), and significantly slow the advancement of breast cancer.260,322 These findings suggest that not only pharmacological interventions but also novel approaches like optogenetics might play a role in modulating the stress response and potentially impacting cancer progression. The integration of such strategies could open new avenues for cancer treatment and further underscores the complex interplay between the nervous system, the immune system, and cancer biology.

Other stress-associated immunomodulatory molecules

The impact of stress on tumor immunity is an area of growing investigation. For example, acute stress has been linked to immune evasion in tumors through increased kisspeptin and its receptor GPR54 levels on immune cells, which affects T cell function via the NR4A1-ERK5 pathway.323 Additionally, endocannabinoids like anandamide are involved in stress response and have been found to negatively affect CTLs via the cannabinoid receptor 2, related to poorer survival in cancer patients.324,325 These insights reveal the complex interplay between stress responses and the immune system’s capacity to detect and fight cancer, potentially leading to new therapeutic approaches targeting stress pathways to boost cancer immunotherapy effectiveness. Recognizing the influence of these molecules on TME and immune function may offer fresh perspectives on the links among stress, immunity, and cancer development.

During sustained stress, the parasympathetic nervous system’s stress-reducing functions, including vagal nerve activity as well as synthesis of Ach, are frequently inhibited.326 However, these parasympathetic reactions enhance the antitumor immune response, suggesting new therapeutic opportunities. Agonists of α7-AChR have shown the effects of anti-inflammation, antiproliferative, and tumor-suppression in both mice and humans.295 Nicotine, a nicotinic ACh receptor agonist, can boost DC activation and CTL responses, improving the efficacy of DC-based antitumor vaccines.327 Additionally, diaphragmatic electrical stimulation in mice increased TFF2 secretion by Tms, which can inhibit MDSC expansion and reduce the carcinogenic potential in mice with inflammatory colon cancer.150 This suggests that cholinergic/parasympathetic stimulation could complement adrenergic/sympathetic inhibition in cancer treatment strategies. The possibility of combining cholinergic activation with adrenergic inhibition for enhanced tumor control through localized immune responses warrants further investigation.

Stress-induced metabolic reprogramming of immune cells

Stress is able to modify metabolism processes within immune cells that circulate in the blood or reside in tissues.328 There is rising proofs that altered metabolism and metabolites will influence the survival and function of leukocytes,329 through disturbing their intracellular energy provision, molecule synthesis, signaling pathways, as well as PTMs.330 GCs or CAs can robustly transfer glucose and lipids into blood, supporting the body’s increased demand for energy and biomolecules.331 They are also related to metabolism changes within immune cells, that in turn affect the responses to tumors.332,333,334,335,336 In mice with mammary cancer, β2-adrenergic signaling significantly promoted immunosuppression of MDSCs and TAMs through metabolism alterations,139,337 that enhanced oxidative phosphorylation, lipids oxidation, and production of prostaglandin E2 (PGE2), however, decreased glycolysis in tumor-infiltrating MDSCs.139 The immunosuppressive response of β2-AR signaling in TAMs can be intensified by upregulation of the COX-2/PGE2 axis.337 T cell antitumor immune function can be impaired by metabolic disturbances, for instance mitochondria damage and low energy availability.338,339 In mice with melanoma and CRC, persistent stress diminished glycolytic pathway as well as oxidative phosphorylation in T cells through β2-AR signaling, leading to T cells exhausted in the TIME.340 In mice with sarcoma, GCs reduced low-affinity Tm through inhibiting lipid metabolic activities, resulting in impaired efficacy of immune checkpoint blockade.341 It has been reported that chronic stress-induced adrenaline in mice and human breast tumors upregulates LDHA and enhances glycolysis.342 LDHA increase as well as excessive lactate within cancer favor immune escape led to poor prognosis of melanoma,343 that associates with decreased levels of the activated T cell nuclear factor (NFAT) and IFN-γ within CTLs.343 Upon elevation of GCs, CAs, as well as 5-HT, neutrophils can speedily secrete several inflammation mediators such as S100A8 and S100A9, thereby facilitating tumor immune evasion,295,344 Additionally, under the state of stress, neutrophils undergo fatty acid oxidation, which promotes the relapse of dormant pulmonary and ovarian malignancies.344 Understanding these complex interactions between stress, immune cell metabolism, and cancer progression is crucial for developing strategies that may enhance the effectiveness of immunotherapies and improve cancer treatment outcomes.

Stress-mediated protein modification

PTMs are able to modulate the immune reactions, which are usually mediated by biologically active metabolites of metabolic reprogramming in immune cells.345 It has been indicated that CAs promote lactate production via anaerobic glycolysis.342,346 Within TME, elevated lactate derived from external and internal origins in TAMs has been verified recently,347 which in accordance with increasing lysine lactylation on histones and transition to an M2-polarized state,347 which can contribute to a tumor-promoting microenvironment.

The regulatory impact of PTMs on immune responses has been well-documented, yet the connections to stress and stress-induced inflammation mediators are just starting to be uncovered.345 O-β-N-acetylglucosamine (O-GlcNAc) transferase catalyzes the addition of O-GlcNAc to the serine or threonine residues of target proteins.348 O-GlcNAcylation is known to enhance the function of lymphocytes, promote neutrophil stimulation, modulate inflammation responses of macrophages, as well as hinder the cytotoxicity of NK cells.348 Notably, the release of GAs or CAs induced by stress usually leads to hyperglycemia and immune dysregulation.349,350 Hyperglycemia has been reported to enhance O-GlcNAcylation of macrophages, which favors M2-type polarization, and afterward aids immune escape within the CRC.351 Palmitoylation, the covalent attachment of palmitic acid to the cysteine residues of target proteins, is primarily catalyzed by zinc finger DHHC domain-containing palmitoyl acyltransferases (ZDHHC),308,351 which exhibit the regional and cell-specific patterns of expression‎ within murine cerebral structure.352 The palmitoyl proteome of neural synapses is susceptible to the effects of chronic stress.353 Degradation of PD-L1 is inhibited by ZDHHC3-induced palmitoylation.354 ZDHHC3 blocking can reduce the PD-L1 expression‎ of tumor cells, thereby enhancing antitumor immunity.354 Thus, the fluctuations in stress-induced metabolites and PTMs could facilitate the precise modulation of cancer immunity. Understanding these complex interactions can provide insights into the development of targeted therapies that modulate the TIME and improve the efficacy of cancer treatments.

Stress management affects cancer immune surveillance

Alleviation of pressure through physical activity and mindfulness- or cognitive-behavior-based methods, for instance, yoga, tai chi, or meditation, has been associated with immunological changes, including reduced inflammation, increased responses of Th1 cells, and enhanced activity of NK cells.355 Psychological interventions have been found to significantly notably minimize the chance of death or relapse within non-metastatic breast cancer patients when they were supplied before surgery and adjuvant therapy,356 as well as enhance life quality and personal happiness for individuals with cancer.357 It is noteworthy that CAs induced by running (not “psychological stress”) can activate YAP/TAZ phosphorylation within mammary carcinoma, subsequently hindering tumor growth of immunodeficient mice,358 which suggests that the transient peak of CAs, intrinsic opioids, or myokines after physical activities could inhibit cancer growth.359,360,361 A study on liver cancer demonstrated that eustress, or positive stress, can enhance the sensitivity of mice to liver cancer immunotherapy. Eustress activates the peripheral sympathetic nervous system in mice, leading to increased levels of NE and epinephrine (EPI) in serum and tumor tissue. The increase in NE and EPI activates β-ARs signaling in tumor cells and tumor-infiltrating myeloid cells. Activation of β-ARs leads to a direct reduction in CCL2 expression‎ in tumor cells and immune cells, reducing the infiltration of TAMs and MDSCs in the TME and enhancing the infiltration and function of CD8+ T cells. This increases sensitivity to ICIs, such as anti-PD-L1 therapy.362 Specifically, some psychotropic medications may exhibit immunostimulatory properties (e.g., affecting the intensity of lymphocytes in the tumor). Psychotropic inhibitors and stimulants used in patients with triple-negative breast cancer are associated with a higher rate of pathological complete response.363 This study underscores the multifaceted impact of stress management on immune function and its potential to influence the effectiveness of cancer therapies. Future studies need to figure out the cell subpopulations and receptors in the TME that interact with them and whether they are specific to a particular tumor type. The exploration of these pathways could lead to novel strategies for enhancing the body’s natural defenses against cancer and improving treatment outcomes.

The brain-gut axis and tumor immunity

The gut and the CNS communicate via the gut-brain axis, which is a bidirectional network between the brain and the gut microbiota.364 It is well-established that the brain regulates the function of the gut through peripheral sympathetic, parasympathetic, and sensory afferent and efferent neurons, as well as the extensively distributed enteric nervous system.365 These regulatory functions include gastrointestinal motility, digestive secretion, immune function, blood flow, and nociception.365,366,367,368 Dysfunctions of the autonomic nervous system (ANS) lead to an imbalance in the regulation of the gut-brain axis, thereby causing dysbiosis.369 Interestingly, there is evidence suggesting that the gut can influence tumor immunity through the synthesis and metabolism of microbial-derived products. Short-chain fatty acids (SCFAs) and amino acid metabolites, such as glutamate, glutamine, and tryptophan. These microbial metabolites can act as signaling molecules, influencing immune responses and potentially contributing to the modulation of antitumor immunity (Fig. 7).

Fig. 7

Neuro-immune regulation maintains gut homeostasis and enhances the efficacy of cancer immunotherapy. The gut and brain communicate through the gut-brain axis (GBA). Brain regulates the function of the gut through peripheral sympathetic, parasympathetic, and sensory nerves, as well as the extensively distributed enteric nervous system (ENS). These regulatory functions include gastrointestinal motility, digestive secretion, immune function, blood flow, and nociception. The nervous and immune systems collaborate to maintain intestinal homeostasis, which is conducive to the growth of probiotics. A. muciniphila and B. pseudolongum are canonical probiotics known for their capacity to produce inosine, which can facilitate the efficacy of ICIs. Inosine enhances the capacity of tumor cells to present tumor-associated antigens, thereby facilitating the recognition and subsequent elimination of these cells. Inosine also plays a role in promoting the activation of immune cells. Specifically, engaging the A2A receptor (A2AR) on T lymphocytes, through the inosine-A2AR-cAMP-PKA signaling cascade, inosine triggers the phosphorylation of cAMP response element-binding protein (pCREB), which in turn upregulates the transcription of IL12Rβ2 and IFN-γ, driving the differentiation and accumulation of Th1 cells within TME. Additionally, inosine serves as an alternative carbon source for CD8+ T cells, particularly under conditions where glucose availability is scarce. This role of inosine helps to alleviate energetic constraints on CD8+ T cells within TME, potentially enhancing their antitumor activities. This figure was created with BioRender (https://biorender.com/)

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Dysbiosis and TIME

Dysbiosis, the dysfunction of the gut microbiota due to an imbalance in the normal gut flora, is recognized as a risk factor for a variety of diseases. Metagenomic sequencing analysis has revealed that an imbalanced gut microbiota can contribute to conditions such as irritable bowel syndrome, diabetes, obesity, and cancers like CRC.370,371,372 In fact, dysbiosis has been demonstrated to promote carcinogenesis in CRC.364,373,374,375,376 Metabolic byproducts resulting from the ecological imbalance of the gut microbiota, such as toxins and cytokines, can lead to inflammation and tumorigenesis, thus contributing to the development of CRC. This suggests that a healthy gut microbiota may play a role in tumor suppression.377 Furthermore, recent studies have provided evidence supporting the role of the gut microbiota, in conjunction with the TME, in modulating responses to antitumor therapies.378,379,380

More specifically, regarding brain tumors, the composition and related functions of the gut microbiota appear to be largely controlled by the interaction between the gut and the CNS through the gut-brain axis.378 The microbial structure in the context of brain tumors, such as gliomas, pituitary adenomas, and meningiomas, has been studied. It has been found that the microbial composition and structural assembly associated with these tumors are dependent on the type of tumor,372,381,382,383,384 highlighting the importance of precision medicine. In the brain, dysbiosis and microbiota-associated metabolic products, such as neurotransmitters, SCFAs, and amino acids, can cause changes in the CNS TME, which may be related to tumors.366,370,374,375,376,377 It was demonstrated that compound K, a metabolite derived from ginsenoside and biotransformed by the gut microbiota, inhibited the migration of glioma cells, which were stimulated by stromal cell-derived factor-1 (SDF-1).385 SDF-1 has previously been shown to positively regulate the growth and migration of glioma cells.386

SCFAs are involved in maintaining the integrity of the BBB, acquiring the mature phenotype of microglia, and the reactivity to brain injury.387,388 In the context of glioma, which is associated with the dysregulation of the gut microbiota, there is an increased permeability of the BBB and immune suppression modulation, including the activity of immune cells such as microglia.387,388 In glioma-bearing mice treated with antibiotics, subsequent dysbiosis of the gut leads to a reduction in cytotoxic NKT cells and alterations in the expression‎ of inflammatory proteins in microglia associated with increased tumor growth, indicating a change in the antitumor activity of immune cells.382 Furthermore, microglia have been shown to promote the progression and angiogenesis of glioma through TREM2 activation,389 a pathway known to be upregulated by SCFAs.390

In metastatic cancer, the activation of receptors for SCFAs (such as propionate and butyrate), specifically free fatty acid receptors (FFAR2 and FFAR3), inhibits the invasive phenotype of breast cancer cells, thereby suppressing metastasis.373,391 These receptors play a crucial role in modulating inflammation and the production of leptin,374 stimulating insulin secretion in response to glucose,375 the secretion of glucagon-like peptide-1,376 and the production of peptide YY.378 Multiple studies have indicated that FFAR2 and FFAR3 are involved in tumor suppression. In CRC, the expression‎ of FFAR2 is significantly reduced, and propionate, a short-chain fatty acid, has been shown to play a significant role in reducing cell proliferation and inducing apoptosis.374,380,381,392,393 These findings suggest that SCFAs and their activation of FFAR2 and FFAR3 receptors could support a model that may aid in the study of the progression of certain cancers.

The gut microbiota influences the efficacy of cancer immunotherapy

The gut microbiota can influence the efficacy of cancer immunotherapy.394,395,396,397,398,399,400,401,402,403 The manipulation of the gut microbiota through methods like fecal microbiota transplantation (FMT),397,404,405,406,407,408 probiotics,409 engineered microbiota, and specific microbial metabolites, such as inosine, can enhance the effectiveness of immunotherapy (Fig. 7). These findings offer new insights into the development of novel cancer treatment strategies based on the microbiome and emphasize the importance of precision medicine.397,410,411,412 Conversely, the disruption of gut microbiota balance through the use of antibiotics may affect the efficacy of ICIs.408,409,413,414,415,416,417 This highlights the delicate relationship between the gut microbiota and the immune system and suggests that maintaining a balanced microbiota is crucial for the success of immunotherapy in cancer treatment. Understanding the complex interactions between the gut microbiota and the immune system is essential for developing strategies that can optimize the response to immunotherapy. This may involve the identification of key microbial species or metabolites that promote a favorable microenvironment for immune cell function and the development of interventions that can modulate the gut microbiota to enhance the therapeutic outcomes for cancer patients.

The impact of tumor immunity on the nervous system

Perineural invasion (PNI), nerve injury and neuritis, cancer, and therapy induce pain

PNI is characterized by the infiltration of tumor cells into adjacent nerves, which can lead to metastatic spread, nerve compression, and pain generation. This phenomenon is associated with a poor prognosis in various cancers, including pancreatic, oral, colorectal, adenoid cystic carcinoma, HNSCC, and prostate cancer.418 TAMs contribute to PNI by releasing cytokines such as IL-6, TNF, CCL5, and CCL18 in response to hypoxic or high-lactate environments, leading to peripheral inflammation and the release of neurotrophic factors, growth factors, and MMPs, which facilitate tumor growth and invasion.419 When nerves are initially damaged by cancer cells, neurons and Schwann cells produce artemin/GFRα3 to repair the nerves.420 However, the abundance of artemin can attract more cancer cells to the site of injury. Infiltrating tumor cells can cause nerve damage and release CCL5, inducing an inflammatory response that promotes the migration of cancer cells expressing CCR5 to the injured nerve, thus enhancing PNI.421 Tumor-derived factors and inflammatory mediators can also activate peripheral sensory fibers, leading to the release of SP that promotes tumor growth. SP enters the tumor, activates NK-1R in cancer cells, and through Src (EGFR, HER2), activates growth factor receptors and the MAPK pathway, including ERK1/2. This leads to increased mRNA expression‎ of MMP2, MMP9, VEGF, and VEGFR, stimulating mitosis, cell proliferation, and preventing apoptosis.422 PNI established connections with distinct brain regions in head and neck cancer. Activation of these neural circuits altered mouse behavior, including reduced nest-building, increased latency to eat a cookie, and decreased wheel running. Disrupting the connecting nerves through genetic or pharmacological means improved all behavioral outcomes in tumor-bearing mice.423 The study suggests that blocking neural connections between tumors and the brain may enhance mental health in cancer patients, although further investigations are needed to establish this link.

In addition to tumor cell invasion, immune cells' infiltration can lead to neuritis. For example, in PDAC, pancreatic nerves are infiltrated by various immune cells, including mast cells, which are associated with the intense abdominal pain experienced in PDAC. TME, characterized by hypoxia and acidity, induces apoptosis in the tumor and peripheral tissues, releasing cellular debris and chemotactic factors that attract inflammatory cells and promote inflammation. The tumor itself triggers immune responses, leading to the aggregation of inflammatory cells and severe inflammation, which promotes tumor growth and infiltration into neural tissues.424 Mitochondrial dysfunction and altered glucose metabolism are typical changes in TME and may be related to the etiology of neurodegenerative diseases and neural injury.425 Oxidative stress can induce chronic neuroinflammation, leading to a functional shift in astrocytes from neurotrophic to neurotoxic, releasing more lactate to enhance their energy support for neurons.426 Following partial peripheral nerve injury, sustained demyelination can promote neural sprouting.427 In cancers such as PDAC, there is an increase in nerve density and size, altering the distribution of nerves within tumors to facilitate signal exchange between cancer cells and nerves. This can be interpreted as pathological neural plasticity induced by tumor-derived factors.428

Cancer-related pain often results from the invasion of sensory neurons by cancer cells, which can directly elicit pain sensations.429 The subsequent neuroinflammatory response can exacerbate pain, and there is a potential link to side effects from therapeutic interventions.430,431 PDAC, known for its intense pain, frequently involves PNI, which is associated with poorer survival outcomes and a diminished quality of life. PNI contributes significantly to cancer pain because of the similarity among signaling molecules implicated in PNI and those associated with pain signaling pathways.429 Cancer pain can present in various forms, including persistent, intermittent, aching, sharp, or neuropathic.432 Within TME, a spectrum of inflammatory mediators can bind to specific receptors on peripheral sensory neurons, converting into pain signals that are conveyed to higher neural centers and perceived as pain.433 Nociceptors, including C-low threshold mechanoreceptors expressing Piezo2 receptor, can be activated through mechanical stimuli, leading to heightened sensitivity to external stimuli and amplifying the perception and response to pain.434

The molecular and cellular basis of cancer pain is complex, impacting various levels of the pain neurocircuitry. Algesic mediators within TME sensitize peripheral sensory neurons, contributing to hyperalgesia and allodynia. These mediators may originate from the tumor and immune cells and include inflammatory factors, cytokines, chemokines, colony-stimulating factors, and neurotrophic factors.112 Changes in TME, such as elevated levels of extracellular ATP and protons, can prompt the production of these mediators. These mediators exert their effects through multiple mechanisms, including direct interaction with receptors or ion channels involved in detecting and signaling noxious stimuli, such as protons through TRPV1 and ASIC receptors.435 They can also induce the sensitization of these receptors/channels by activating kinases, which phosphorylate TRPV1, leading to its sensitization, or by upregulating the expression‎ of these receptors/channels. Nerve growth factor (NGF), by binding to its TrkA receptor, can induce high expression‎ of TRPV1 and ASIC3, along with neurotransmitters that regulate nociceptor excitability, such as SP, CGRP, BDNF, and various sodium and calcium channels.435 The sensitization of TRPV1 can also occur through interplay with other receptors, including P2X3 and NMDA.436,437 Inflammatory mediators produced by immune cells contribute to the exacerbation and maintenance of pain. Pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, as well as other inflammatory mediators like PGE2, play a role in cancer pain across various cancer types.438,439 Therapies targeting pro-inflammatory molecules are becoming potential solutions for managing pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently employed in clinical practice to provide additional pain relief in conjunction with more potent analgesics.440

Cancer-related pain may arise from increased tissue innervation due to ectopic neural sprouting as well. In TME, neurotrophic factors such as NGF, BDNF, GDNF, and VEGF are released, leading to neural sprouting.441 Molecules engaged in axon guidance, including those from the ephrin and netrin families, contribute to neural sprouting within tumors. This disordered sprouting leads to an overall elevation in nerve fiber intensity and the formation of neuroma-like structures.435 Neural sprouting can disrupt the physiological separation of sensory and sympathetic nerves, with the activation of sensory neurons by sympathetic nerves potentially leading to movement-induced pain.442,443

The aim of cancer pain management is to reduce suffering, enhance quality of life, and minimize side effects. Treatment strategies include pharmacological therapies (opioids, NSAIDs, antidepressants, anticonvulsants), non-pharmacological interventions (physical, psychological therapies, neurostimulation), and tumor-directed treatments (surgery, chemotherapy, radiotherapy, immunotherapy). Personalized treatment plans should be adjusted based on disease progression and treatment responses.444

Paraneoplastic neurological syndromes (PNS)

PNS refers to a group of neurological symptoms that occur in cancer patients. These symptoms are not caused by direct tumor invasion, distant metastasis, infection, metabolic abnormalities, or side effects of treatment, but are mediated by the body’s immune response to antigens expressed on tumor cells, which are also expressed in the host’s nervous system.445 Antigens released after tumor cell apoptosis are presented to Th cells in peripheral lymph nodes by antigen-presenting cells. Subsequently, CD4+ helper T cells activate antigen-specific B cells to become antibody-producing plasma cells. These antigens are divided into cell surface antigens and intracellular antigens.446,447,448 The mechanisms of disease targeting these two types of antigens differ. Antibodies against intracellular antigens are not directly pathogenic but serve as biomarkers for cytotoxic T cell-mediated tissue damage.449 CD8+ T cell infiltration has been found in the neural tissues of patients with antibodies against intracellular antigens.450,451,452 In contrast, antibodies against cell surface antigens bind in vivo, and numerous studies have elucidated the direct pathogenic mechanisms.453,454 For example, antibodies against AMPA-R, NMDA-R, and GABA-Rs cause neuronal dysfunction by receptor cross-linking and internalization, leading to a reduction in cell surface receptor density.450,455,456,457,458 On the other hand, GABAR antibodies directly impair receptor function without causing internalization.459 Aquaporin-4 antibodies mediate antigen internalization and complement-induced cytotoxicity, while LGI1 antibodies affect protein-protein interactions with their receptor ADAM22.460,461

The clinical presentation of neurological disorders can vary depending on the specific antibodies induced by the particular tumor.462,463 These disorders often manifest as a diverse range of neurological symptoms, such as paraneoplastic encephalitis,464 paraneoplastic cerebellar degeneration,465 neuritis,466,467,468,469,470 and myasthenia gravis syndrome462 (Table 1).

Table 1 Cancer types associated with paraneoplastic neurologic disorders

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In a study on 26 ovarian cancer tumors associated with Yo-paraneoplastic cerebellar degeneration (Yo-PCD), the immune contexture of the tumors and the genetic status of two tumor-associated antigens (Yo antigens), CDR2 and CDR2L, were analyzed. The study found that Yo-PCD tumors had a richer infiltration of T and B cells compared to control tumors, occasionally forming tertiary lymphoid structures with CDR2L protein deposits. Immune cells were primarily located near apoptotic tumor cells, indicating an immune attack on the tumor. Moreover, 65% of Yo-PCD tumors had at least one somatic mutation in the Yo-antigen genes, mainly missense mutations, compared to the control group.462 In patients with breast cancer combined with Yo-PCD, these breast cancers were predominantly aggressive, HER2-positive, and hormone receptor-negative, with early lymph node metastasis. All Yo-PCD breast cancers carried at least one genetic variation leading to the overexpression‎ of Yo antigens.471 Anti-Kelch-like protein 11 (KLHL11) paraneoplastic encephalitis is commonly seen in testicular germ cell tumors.464,472 A retrospective identification of 31 KLHL11 IgG-positive cases was conducted, and human leukocyte antigen typing and assessment of KLHL11-specific T cell responses were performed. The study found no increased activation of CD4+ and CD8+ T cells in response to KLHL11 antigen stimulation in healthy controls compared to KLHL11 IgG-positive patients.472 In SCLC, paraneoplastic encephalitis associated with anti-Hu, GABABR, and anti-voltage-gated calcium channels has been observed.464,473,474,475,476 In patients with anti-GABABR PNS, there is a common gain of chromosome 5q, containing KCTD16, while losses are often seen in anti-Hu and control patients.25 Transcriptome analysis revealed the specific overexpression‎ of KCTD16 in anti-GABABR PNS.25 In patients with late-onset paraneoplastic encephalitis associated with prostate adenocarcinoma, these patients exhibited psychiatric symptoms related to autoimmunity against the DRD2, indicating that in some cases, tumors may trigger an autoimmune response against dopamine receptors, leading to neurological symptoms.477 These studies show that tumor-mediated immune responses can damage the nervous system, with diverse manifestations that may precede the diagnosis of the tumor.

In addition to immune responses mediated by tumor-associated antibodies and antigens that can lead to PNS, the binding of cytokines to receptors can also cause neurologic dysfunction. For instance, the binding of GDF15 to GFRAL receptors in the brainstem can induce anorexia, leading to reduced food intake and subsequent cachexia in cancer patients.478,479,480,481 GDF15 has been found to be expressed in tumor cells, TAMs, and fibroblasts,482,483 and its levels are elevated in the serum of cancer patients or mice.481,484,485,486 Neutralizing GDF15 or pharmacologically inhibiting it can reverse anorexia and weight loss in mice.481 However, it has been found that neutralizing GDF15 with a potent monoclonal antibody (mAB2) did not improve anorexia and weight loss caused by low-dose lipopolysaccharide-induced inflammation.487 Therefore, further studies are needed to assess the efficacy of targeting GDF15 therapies.

The treatment of paraneoplastic syndromes encompasses neuroimmunological therapies, cancer-specific treatments, and symptomatic therapies. Diseases associated with cell surface antibodies respond better to immunotherapy than other paraneoplastic diseases, while those associated with intracellular antineuronal antibodies respond poorly to immunotherapy.488 Commonly used medications in immunotherapy include corticosteroids, intravenous immunoglobulins, immunosuppressive agents (such as cyclophosphamide), and plasmapheresis.489 In patients with anti-NMDA-R encephalitis, rituximab is often used early in the course of severe neurological disease.489 Under the guidance of oncology and surgery, cancer treatment may coincide with the stabilization or improvement of neurological symptoms. Some patients with anti-NMDA-R encephalitis have significant improvement in neurological symptoms after the removal of ovarian teratomas. To improve neurological symptoms, various treatments are employed for conditions such as myasthenia gravis (pyridostigmine),490 Parkinson’s syndrome (levodopa), dystonia (benztropine or botulinum toxin), epilepsy (Sodium Valproate),491 myoclonus (benzodiazepines).490,492

ICIs induced neurological disorders

ICIs have revolutionized cancer therapy, but their systemic activity can lead to a broad range of immune-related adverse effects on the nervous system (nirAEs),493,494 which include peripheral neuropathy,495,496 myositis,496,497,498 myasthenia gravis,496,499,500,501,502 Guillain-Barré syndrome,503,504,505 encephalitis, and other CNS disorders.506 Although the incidence is relatively low (about 1%–6%), the potential severity and the possibility of needing to interrupt cancer treatment make these side effects particularly significant. Despite the exact mechanisms of neurotoxicity induced by ICIs not being fully understood, the enhancement of immune responses mediated by CD8+ T cells through the blockade of tumor suppressive signals appears to play a decisive role.507,508,509 Concurrently, CD4+ T cells are also of significant importance. In a patient with metastatic melanoma who developed fatal encephalitis following anti-PD-1 therapy, spatial and multi-omic analyses revealed a significant enrichment of activated memory CD4+ T cells in the inflamed brain region. A highly oligoclonal T cell receptor (TCR) repertoire was identified and localized to activated memory cytotoxic (CD45RO+GZMB+Ki67+) CD4+ T cells.369 In addition, mechanisms such as the downregulation of Tregs, the cross-presentation of neoantigens, epitope spreading, genetic predisposition, and alterations in the microbiome are involved in this process.510,511

Current treatment recommendations include discontinuation or suspension of immunotherapy and the use of high-dose corticosteroids, intravenous immunoglobulins, plasmapheresis, or other immunosuppressive drugs in refractory cases.495,508,512 However, further structured study is needed to better understand and optimize the clinical management of neuro-immune-related adverse events.507 The recognition of these neurological side effects emphasizes the importance of a multidisciplinary approach to cancer care, integrating neurology and oncology to manage the complex interplay between immunotherapy and the nervous system. It also underscores the need for ongoing clinical vigilance and research to improve patient safety and outcomes in the era of immunotherapy.

The potential of neuroimmunotherapy in cancer treatment

The growing data on neuro-immune bidirectional communication within the TME suggests that targeting the nervous system holds promise as a therapeutic approach. This strategy can strengthen existing treatments as well as enhance the prognosis of patients. In TME, the modulation of adrenergic signaling through physiology, pharmacology, and genetics has shown that reducing adrenergic stress leads to an increase in CD8+ T cells infiltration, a lower rate of PD-1 receptor expression‎,315,318 and a better effect of anti-PD-1 treatment.315 A preclinical study reported that in mice with fibrosarcoma as well as CRC, the concurrent use of propranolol and anti-CTLA-4 antibody increased T lymphocytes and reduced the infiltration of MDSCs into TME, significantly enhancing the effectiveness of anti-CTLA-4 therapy.144

Clinical trials completed

Clinical trials targeting the neuro-immune axis in cancer were being assessed based on the regulatory effects of drugs on neural signaling (Table 2). These included direct alteration of neural function (e.g., lidocaine) and targeting downstream activities of the nervous system following stimulation and subsequent neurotransmitter release (e.g., propranolol). Phase I clinical trial of combination propranolol and pembrolizumab in locally advanced and metastatic melanoma (NCT03384836) showed no dose-limiting toxicities, and a response rate of 78%. Patients treated had higher levels of IFN-γ, while lower levels of IL-6.513 Preoperative β-blockade with propranolol can reduce metastasis biomarkers of breast cancer in a phase II randomized trial (ACTRN12615000889550).318 For instance, reduced intratumoral mesenchymal polarization, elevated tumor infiltration of CD68+ macrophages, and CD8+ T cells were observed in patients treated in early-stage surgically resectable breast cancer. Another clinical trial also showed an increase in tumor-infiltrating CD8+ T cells and the expression‎ of GzmB in CRC patients after one week of administration of propranolol (NCT03245554). In addition, the intratumoral level of phosphorylated ERK was down-regulated. However, there was no significant difference in Ki67 or the expression‎ of p-AKT and p-MEK.514 This indicates that propranolol suppresses tumor growth by enhancing the infiltration of CD8+ T cells into the TME, rather than directly affecting the tumor itself, which is consistent with the aforementioned observation that the application of propranolol in mice with melanoma leads to an increase in tumor-infiltrating CD8+ T cells. In the clinical study combined application of propranolol and COX-2 inhibitor in early-stage breast cancer, it was found that various cellular and molecular pathways contributed to metastasis, and the recurrence of disease was suppressed, and tumor-infiltrating monocytes decreased, while tumor-infiltrating B cells increased. Additionally, the expression‎ of CD11a on circulating NK cells was upregulated, whereas the activity of CD16− monocytes was suppressed (NCT00502684).319 However, this study involved the combined use of two drugs, and it does not demonstrate that these antitumor immune effects are mediated by propranolol. The concurrent administration of propranolol and COX-2 inhibitor in another clinical trial (NCT00888797) supported the effect of them on the enhancement of antitumor immunity by elevating NK cells in TME.515 Although propranolol has shown promising effects in improving the TIME in these clinical studies, the impact on tumor recurrence rates and long-term survival outcomes of patients requires further observation and investigation. Additionally, there is a lack of assessment for β-ARs in cancer specimens. The variation in β-AR levels across different tissues may influence the therapeutic response to β-AR blockers. The patients were not effectively stratified, which may introduce bias in the study outcomes. A potential solution is to assess the expression‎ of β-receptors in cancer specimens pathologically before the commencement of the clinical trial. This approach could help in identifying patients who are more likely to respond to propranolol, thereby enhancing the efficacy of the treatment regimen. Furthermore, the number of patients in these clinical studies is relatively small, necessitating the inclusion of more patients to validate the efficacy of propranolol, and precise stratification of responders and non-responders is essential to maximize the benefit for oncological patients.

Table 2 Summary of the completed clinical trials targeting the neuro-immune axis in cancer

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Simultaneously, the voltage-gated sodium channel Nav1.8 has been studied for its potential anti-cholinergic effects in the TME. An enhanced antitumor immunity was found after the use of lidocaine, a sodium channel blocker that targets voltage-gated sodium channels on nerve fibers and possesses anti-cholinergic effects.516,517,518 In a clinical trial examining the impact of lidocaine on 120 breast cancer patients (NCT02839668),519 these patients underwent surgical resection and received intravenous lidocaine as an anti-cancer treatment. It has been shown that lidocaine could reduce the release of MMP3, neutrophil extracellular traps (NETs), as well as myeloperoxidase, supporting that the recurrence rate would be reduced if lidocaine were administered for therapeutic purposes.519 An additional clinical trial (ChiCTR2000030629) corroborated the notion that lidocaine bolsters antitumor immunity, as evidenced by its effects in 95 patients with NSCLC.520 However, the clinical trial for pancreatic cancer, lidocaine did not alter overall or disease-free survival (NCT03245346).521 Lidocaine exhibited unfavorable effects in pancreatic cancer, and the underlying reasons may be that the cholinergic nervous system exerts an anti-pancreatic cancer effect, while lidocaine blocks cholinergic neurotransmission. Consequently, the use of lidocaine in pancreatic cancer may not yield favorable outcomes. More investigations are needed to elucidate the molecular mechanism.

Clinical trials ongoing

A multitude of clinical trials focusing on neuroimmunotherapy are either in progress or have been completed but not yet published (Table 3). A substantial proportion of these trials explore the application of propranolol, expanding to a broader spectrum of tumor types, including gastrointestinal, prostate, and fallopian tube cancers. Nadolol, a nxxonselective β-AR blocker, is also under investigation in clinical studies for the treatment of infantile hemangiomas.44,522 Compared to propranolol, nadolol offers the advantage of a longer duration of action and greater convenience, potentially leading to its application in an even wider range of tumor types in the future. Donepezil, a drug utilized for the treatment of Alzheimer’s disease, inhibits AchE in the brain, thereby elevating Ach levels. Studies have applied donepezil to brain tumor, breast cancer, and head and neck cancer, with the aim of improving cognitive and emotional impairments following radiotherapy and chemotherapy in cancer patients. It is hypothesized that donepezil may reduce stress levels and enhance antitumor immunity. Additionally, bethanechol, a muscarinic agonist, is being investigated in clinical studies for pancreatic cancer. Investigators hypothesize that bethanechol treatment will alter nerve conduction within tumors by stimulating the parasympathetic nervous system, which may reduce tumor proliferation, macrophage activation, and decrease human cluster of CD44+ CSCs. Concurrently, the application of lidocaine has been expanded to more tumor types, such as colon and breast cancers.

Table 3 Ongoing clinical trials targeting neuro-immune axis in cancer

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In addition, there are numerous neuro-immune targets with the potential for further clinical research. For instance, drugs targeting CGRP, such as the monoclonal antibody Erenumab, have been commercialized and approved for the treatment of migraine. They hold significant promise in the treatment of tumors like metastatic melanoma, head and neck cancers, and pancreatic cancer,124,127 but their efficacy needs to be confirmed through well-designed clinical trials. Antidepressants targeting 5-HT have been shown to enhance antitumor immunity in mice,153 yet there is a lack of clinical trial evidence to support it. Modulating circadian rhythm genes and manipulating the brain-gut axis to strengthen antitumor immunity also have potential therapeutic value, warranting further investigations.

Conclusion and future directions

Research on the interaction between the nervous and immune systems, especially regarding the neuro-immune-cancer axis (Table 4), remains limited. Neuronal components within TME hold significant research value, as they play a pivotal role in cancer. They modulate the immune response within TME by releasing neurotransmitters and neuropeptides, influencing the activity of immune cells. Pain and symptoms associated with cancer may be related to the activation of neuronal components, and understanding these mechanisms could aid in the development of more effective pain management strategies. Neuronal components may also affect the tumor response to therapies, including chemotherapy, radiotherapy, and immunotherapy. The presence of neural components or specific neuronal markers may serve as biomarkers for predicting tumor prognosis and therapeutic responses. Investigating neural components in TME may reveal new drug targets, opening avenues for targeted therapeutic strategies. Furthermore, these components are associated with tumor invasiveness and metastasis, and understanding this relationship could aid in developing strategies to prevent tumor spread. Examining how tumors affect the nervous system may inform strategies to minimize neurological damage during cancer treatment.

Table 4 Cancer types that involve in neuro-immune crosstalk

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Targeting the neuro-immune-cancer axis may emerge as a more comprehensive, holistic, and effective novel approach to cancer treatment. Elucidating the molecular mechanisms of them in TME, including neurotransmitters, cytokines, receptors, and signaling pathways, is crucial for precise tumor therapy. Depending on the role of neural components in different TME, selectively enhancing or blocking neural transmission may augment the efficacy of existing antitumor treatments. Systemic stress, stress disorders, mood disorders, and circadian rhythm disruptions can profoundly impact the homeostasis of the immune system, the growth of tumors, and the response to treatment. The appropriate application of existing medications such as sedatives, anti-anxiety and antidepressant drugs, and anti-epileptic drugs combined with antitumor therapy may improve patients’ quality of life and extend survival time.

Studying the neuro-immune-cancer axis will face numerous challenges in the future: both the nervous and immune systems consist of a vast array of different cell types, each with distinct functions and interactions. Distinguishing and investigating these cell types requires highly specialized techniques. Neuro-immune interactions involve complex molecular mechanisms. Unraveling these mechanisms necessitates precise molecular biology tools. Neuro-immune interactions may have different functions and effects at various times and places. Studying this spatiotemporal control requires meticulous experimental design and analytical methods. The interplay between the nervous and immune systems may interact with other systems (such as the endocrine system), and studying these multi-system interactions requires interdisciplinary approaches. Although animal models are vital tools for this field, they may not fully replicate the conditions of human cancers. The data generated from neuro-immune research is voluminous and complex, necessitating sophisticated bioinformatics tools and statistical methods for processing and interpretation.

Overcoming technical hurdles in studying neuro-immune interactions in TME demands collaboration across neuroscience, immunology, oncology, pathology, and pharmacology. It involves innovative designs, advanced techniques, and strong data analysis. As science progresses, these challenges are being met, leading to deeper insights into neuro-immune-cancer dynamics. Continued interdisciplinary efforts are key to developing new cancer therapies targeting these interactions.

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