항암 약물에 잘 듣는 몸 : fasting 상태.. 최신논문 탐구!!

[문형철]

끊임없이 분열, 무한증식하는 암세포

normal cell cycle의 정상세포

malnutrition이 아닌 fasting 몸 상태를 만들면

normal cell cycle의 정상세포는 세포분열을 최소화한다.

이 상태에서 항암 약물, 고농도 비타민 C, 항암 한약을 투여하면

이 상태에서 Submaximal exercise를 지속하면

암세포는 어떻게 될까?

living with cancer의 길!!

2020년 5월 5일 게재된 오픈액세스 리뷰입니다.

단기간 단식(STF)이 세포·동물 종양 모델에서

항암치료를 어떻게 강화하는지, 기전·초기 임상·한계·다음 단계를 정리한 논문입니다.

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한 줄 핵심

암세포는

영양·성장인자 의존도가 높고 적응력이 약하다.

24–72시간(때로는 최대 5일) 단식으로 혈당·인슐린·IGF-1을 떨어뜨리면,

정상세포는 스트레스에 강해지고(DSR) 암세포는 화학요법에 더 잘 죽게 된다(DSS).

다만 대규모 RCT는 아직 없고,

악액질·이질성·전이(EMT) 문제는 주의가 필요하다.

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단식 전략 분류 (논문 Table 1)

방법내                                                                                         용기간

STF	거의 0 kcal	보통 24–72시간 (일부 5일)
DR	칼로리 20–40% 장기 제한	수주–수개월. 만성 체중감소·면역저하 위험
IF	격일 또는 주 2일 500–700 kcal	만성 체중감소는 상대적으로 적음
FMD	저칼로리·저단백·저당 모사식	예: 1일 ~50%, 2–4일 ~10% 후 재급식
PFRC	1–2일 STF + 5–6일 자유식 주기	내약성·생존 연장 보고와 재급식 시 증식 우려가 공존

임상에서 당장 쓰기 쉬운 것은 항암제 전후 짧은 STF이고, 장기 DR은 암 환자에서 체중·창상·면역 문제로 제한적입니다.

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기전 (모델 근거)

단식 후 간 글리코겐이 약 30시간 내 고갈되고 당생성이 시작됩니다. 동시에:

• 성장축 억제: IGF-1↓, IGFBP-1↑(72시간 STF에서 약 11배), 인슐린↓
• 에너지 센서: AMPK↑ → SIRT1↑ → IGF-1 생성 억제
• 증식 경로 차단: PI3K/Akt/mTOR↓, RAS/MAPK↓
• Warburg 의존 암세포는 포도당·성장인자가 줄면 적응이 어렵고, 정상세포는 보호 모드로 들어갑니다 (DSR / DSS).
• 전이·EMT: 저혈당·저혈청 모사배지(FMM)만으로도 췌장암 세포 이동이 줄고, IGF-1R–β-catenin/E-cadherin 축을 통해 EMT가 약해질 수 있다는 보고. 다만 아스파라긴 등 특정 아미노산은 CTC·전이를 촉진할 수 있어 단식이 전이에 항상 이롭다고 단정할 수는 없습니다.

항암제와 병용 시 유방암·신경모세포종·대장암 마우스에서 종양 진행 지연, 흑색종 전이 장기 수 감소, 생존 연장이 보고되었습니다. 정상 조직은 독성으로부터 상대적으로 보호됩니다.

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초기 임상 (소규모, 2020 시점)

논문이 인용한 당시 결과는 독성 완화·내약성 중심입니다. 대규모 생존 이득은 아직 없습니다.

• HER2 음성 조기 유방암 TAC(독소루비신 등) 전후 24시간 STF → 혈액독성 감소, PBMC DNA 손상 회복 촉진
• 다양한 암(전립선·유방·식도 등)에서 항암 48시간 전 / 5시간 후 단식 → 오심·구토·점막염이 거의 없음 (n=10)
• 유방·난소암 교차시험: 항암 36시간 전 + 24시간 후 STF → 내약 가능, QoL↑, 피로↓
• 백금계 항암 중 72시간 단식 → 백혈구 DNA 손상 감소

당시 최소 4건의 진행 중 임상시험이 있었습니다. 결론은 “안전·독성 감소 신호는 있으나, 생존·무병생존을 말할 RCT는 없다”입니다.

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논문이 강조한 한계 (임상 적용 시 핵심)

1. 악액질·근감소·영양실조
   암 환자에서 유병률이 높고(최대 ~80%), 단식이 이를 악화시킬 수 있음. 췌장암 악액질 등에서는 금기에 가깝다고 보는 편이 안전합니다.
2. 암종·병기 비교 데이터 부족
   유방·난소·전립선·식도·폐·자궁 등에서 “쓸 수 있다”는 수준이지, 병기별 효과 차이는 검증되지 않음.
3. 종양 이질성
   동일 장기 안에서도 관류·영양 이용(포도당 vs 지방산·젖산·케톤)이 다름. 세포주·이종이식만으로는 단식 파라미터를 정하기 어렵다.
4. EMT·전이
   단식이 EMT를 억제할 수도, 특정 대사물(아스파라긴 등) 맥락에서는 전이를 도울 수도 있음.
5. 프로토콜 미표준화
   몇 시간 전부터, 무엇을 마실지, 재급식 타이밍이 환자·약제마다 다름.

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다음 단계로 제안한 것

• FMD: 완전 단식보다 내약성이 낫고 IGF-1을 낮추며, 항암·면역치료와 병용 시 림프구 전구세포·TIL↑, Treg↓, HO-1↓ 보고.
• PFRC: 주기적 단식–재급식으로 내약·생존 이득 보고가 있으나, 재급식 시 간·대장 과증식·전암병변 우려도 있음.
• 면역치료와의 조합: 항암으로 인한 면역억제를 완화하고 HSC 보호·재생에 도움이 될 수 있음.
• 필요 과제: 환자 아형(암종·대사상태·p53 등)별 맞춤, 장기간 효과, 임상적으로 의미 있는 종양 모델(이질성 반영).

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임상적으로 가져갈 점 (2020 리뷰 기준)

단식은 “항암제를 대체하는 치료”가 아니라 치료 지수(efficacy/toxicity)를 넓히려는 보조 전략입니다.
체중 유지가 되고 악액질이 없는 환자에서, 항암 주기 전후 짧은 STF 또는 FMD를 고려할 여지는 있으나, 당시에도 저자들은 무작위 대조로 생존 이득이 증명되지 않았다고 분명히 적었습니

Fig. 1은 이 논문의 핵심 도식입니다.

단식(STF)이

**간 대사 → 혈당·IGF 축 → 정상세포 vs 암세포의 스트레스 반응 차이(DSR)**로 이어지는 흐름을

세 단계로 그린 것입니다.

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① 글리코겐 분해 (glycogenolysis)

단식 → 에피네프린(EPI)·글루카곤(Gluc) 상승
→ 간에서 AC → cAMP↑ → PKA 활성화
→ glycogen phosphorylase가 글리코겐을 깨서 **포도당(GLU)**을 만듦
단식이 길어지면 간 글리코겐이 고갈됩니다(논문: 대략 30시간 전후).

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② 당생성 (gluconeogenesis)

글리코겐이 바닥나면 간이 새로 포도당을 만듭니다.
기질: 글리세롤(Gly), 젖산(lactate), 아미노산(AA)
중간체: GAP, PEP
전사인자 CREB(PKA가 Ser133 인산화)가 당생성 유전자를 켭니다.
목적은 뇌·근육 등 정상 조직에 최소한의 포도당을 공급하는 것입니다.

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③ STF의 전신 신호와 DSR (이 그림의 핵심)

STF의 결과:

• IGF-1 ↓
• IGFBP ↑ (순환 IGF-1을 묶어서 작용을 막음)

여기서 정상세포와 암세포가 갈라집니다.

정상세포                                                                                                  암세포

성장 경로	Akt↓, Ras↓, proto-oncogene↓	Akt↑, Ras↑, oncogene이 켜진 채 유지되는 경향
모드	Maintenance (유지·보호)	Growth (증식 프로그램을 못 끔)
항암제	독성에 상대적 저항 → DSR	오히려 더 잘 죽음 (DSS, 그림 왼쪽 루프)

왼쪽 순환 화살표가 바로 그 대비입니다.
같은 단식·같은 항암제인데, 정상세포는 “유지 모드”로 들어가 보호되고, 암세포는 종양유전자·Akt/Ras가 켜져 있어 스트레스에 더 취약해집니다.

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임상적으로 이 그림이 말하는 것

단식의 효과는 “칼로리를 깎는다”가 아니라:

1. 간에서 글리코겐 → 당생성으로 전신 연료를 재배치하고
2. **IGF-1↓ / IGFBP↑**로 성장 신호를 낮추며
3. 그 환경에서만 **DSR(정상 보호) + 항암제 감수성 증가(암)**가 동시에 일어난다는 것입니다.

그래서 논문은 STF를 항암 전후 짧은 창에 두는 이유를 이 축(혈당·IGF·Akt/Ras)으로 설명합니다.
악액질 환자에서는 ②의 기질(AA, 지방)이 이미 고갈되어 있어 같은 회로를 안전하게 돌리기 어렵다는 점도 이 그림과 맞물립니다.

https://pmc.ncbi.nlm.nih.gov/articles/PMC9530862/

일본암학회 공식지(Cancer Science)에 실린

2022년 서술적 리뷰입니다.

단식·간헐적 단식이 암을 어떻게 건드리는지 기전을 모으고,

당시까지의 **사람 임상(특히 IF)**을 정리한 글입니다.

저자 결론은 한 줄입니다.
장기간·주기적 단식을 표준 치료와 병용하면, 무병 생존·치료 효과·부작용 감소에 도움이 될 수 있다.
단독 치료 주장은 아닙니다.

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단식이 몸에서 하는 일

금식하면 글리코겐 → 지방(유리지방산·글리세롤) → 케톤으로 연료가 바뀝니다.

뇌는 포도당+케톤, 다른 조직은 지방산을 씁니다.

혈당은 대략 70 mg/dL 근처로 유지됩니다.

암과 직접 맞닿는 변화:

내려가는 것                                                           올라가는 것

포도당, 인슐린, IGF-1, 렙틴	아디포넥틴, IGFBP1, FGF21
MAPK, heme oxygenase-1	케톤(BHB), NAD+, SIRT3/4
	자가포식 인자 (Atg, LC3, Beclin1, p62, Sirt1, LAMP2)

• FGF21이 간 STAT5를 막아 IGF-1을 낮춤.
• IGFBP1이 순환 IGF-1을 묶어 수용체 결합을 줄임.
• IGF-1 저하는 대장·전립선·유방암 위험 및 항암 내약성과 자주 연결됨.
• BHB는 내인성 HDAC 억제제로 산화스트레스 신호와 종양 성장을 누를 수 있음.
• 글루코코르티코이드·아드레날린도 혈당 유지·지방분해에 관여한다고만 언급 (Nature 논문처럼 GR을 주인공으로 두지 않음).

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암세포 vs 정상세포 (논문 Fig. 2 요지)

정상세포: 성장 신호를 끄고 분열을 늦춤 → 항암제 독성에서 상대적으로 보호 (differential stress resistance).

암세포: RAS/AKT 등으로 성장 신호를 끄지 못함 → 같은 환경에서 더 취약.

추가로 정리한 경로:

1. 해당과정 → OXPHOS 전환 압력 → ROS ↑ → p53, DNA 손상, 세포사 (항암과 시너지).
2. 자가포식 활성화 → 손상 소기관 제거 또는 특정 조건에서 세포사.
   주의: 자가포식은 종양억제와 치료저항 양날. 사람에서 IF가 자가포식을 얼마나 켜는지는 당시에도 미확정.
3. 면역: CD39/CD73 억제 → 세포외 ATP 축적 → Treg·M2 억제, CD8+ T세포 활성화. HO-1 억제와도 연결.
4. Sirtuin(NAD+ 의존)으로 정상세포 보호.

1. 성장·당 신호를 끊음 (왼쪽) 단식이 낮추는 것:

• 포도당 → 호기성 해당과정(Warburg) 연료 감소
• IGF-1, 인슐린
• MAPK
• heme oxygenase-1 (HO-1)

당·인슐린·IGF-1이 줄면 아래쪽 mTOR·AKT도 같이 내려갑니다.

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2. 미토콘드리아·ROS·항암 시너지 (위·핵)

당이 부족해지면 암세포는 해당과정에서 OXPHOS 쪽으로 밀립니다.

• ADP/ATP 변화 → AMPK 활성화 → mTOR 추가 억제
• OXPHOS ↑ → ROS ↑
• 항암제(Chemotherapy)가 같은 핵으로 들어옴
• ROS + 항암제 → DNA 손상, p53 활성화 → 세포사

단식 단독 세포사라기보다, 대사 스트레스로 항암제에 더 잘 죽게 만드는 그림입니다.

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3. 자가포식 (가운데)

AMPK ↑ / mTOR·AKT ↓ 와 함께
Atg, LC3, Beclin1, p62, Sirt1, LAMP2가 올라가 autophagy가 켜집니다.
도에서는 자가포식이 세포사와 면역 쪽으로 이어지게 그려져 있습니다.

리뷰 본문은 동시에 말합니다.
자가포식은 종양억제일 수도, 치료저항일 수도 있다.

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4. 면역 (오른쪽)

• 자가포식·대사 변화 → CD73, CD39 ↓
• 세포외 ATP 축적
• Treg·M2 대식세포는 억제 쪽으로
• CD8+ 세포독성 T세포 활성화
• HO-1 억제 → apoptosis ↑ → 다시 CD8 쪽으로

즉 “암세포만 굶긴다”가 아니라 억제성 미세환경을 조금 푸는 축도 그려져 있습니다.

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임상 쪽 톤 (2022 기준)

• 사람 연구는 대체로 소수·단기·젊은 층에 치우침.
• IF 단기 RCT에서 암 위험 인자(당, 인슐린, 렙틴 ↓, 아디포넥틴 ↑)는 좋아지는 경우가 있음.
• 장기 IF가 인슐린 감수성·CRP를 분명히 개선했는지는 약함.
• 초점은 항암 효과 증폭 + 부작용 완화 + QoL.
• 권고 형태는 “물만 마시는 장기간 단식으로 암을 고친다”가 아니라
  주기적·비교적 긴 단식 + 표준 항암입니다.

1. 간 (LIVER)
글리코겐 → 포도당이 먼저 떨어지고,
피루브산 경로와 지방산·글리세롤·아미노산으로 케톤을 만듭니다.
포도당 신생합성(gluconeogenesis)도 같이 돌아갑니다.
표시된 효과: 인슐린 감수성 ↑, 케톤 생성 ↑.

2. 지방조직 (ADIPOSE)
중성지방 → 지방산 + 글리세롤.
지방산은 간·근육으로, 글리세롤은 간의 당 신생에 쓰입니다.
표시: 지방산 동원 ↑, 염증 ↓.

3. 근육 (MUSCLE)
단백 → 아미노산 → 간으로 가서 당 신생에 기여할 수 있음.
지방산 → acetyl-CoA → 케톤.
표시: 자가포식 ↑, 인슐린 감수성 ↑.
(오래 굶으면 근단백 분해가 커지므로, 악액질 환자에서는 이 화살표가 곧 위험이기도 합니다.)

4. 뇌 (BRAIN)
처음엔 포도당, 단식이 길어지면 케톤을 같이 씁니다.
표시: 시냅스 가소성, 인지, 신경발생 ↑, 염증 ↓, 자가포식 ↑.
점선 화살표는 장기 사이 연료·대사산물 이동입니다. 간에서 나온 케톤이 뇌와 근육으로 가고, 지방·근육에서 나온 기질이 간으로 돌아갑니다.

논문이 정리한 기전

1. Warburg 효과 / 대사 취약성
   암세포는 산소가 있어도 해당과정(glucose)에 의존합니다. 단식으로 혈당·인슐린·IGF-1이 떨어지면 정상세포는 지방산·케톤으로 전환하지만, 암세포는 적응이 어렵습니다.
2. 자가포식(autophagy)
   단식은 동화 → 이화 상태로 전환해 손상 소기관·단백질을 청소합니다. 종양 내 대사 폐기물·기능 저하 미토콘드리아 제거와 관련해 논의됩니다.
3. Differential stress resistance (차별적 스트레스 저항)
   정상세포는 대사·성장 신호를 낮추고 보호 상태로 들어가 항암·방사선 독성이 줄어듭니다. 암세포는 계속 분열하므로 DNA 손상에 더 취약해집니다.
4. 면역
   전임상에서 NK세포·세포독성 T세포 활성 증가, 일부 염증성 사이토카인 감소가 보고됩니다.
5. apoptosis
   p53, BAX, caspase 증가 / Bcl-2 감소 등으로 암세포 사멸 경로가 강화될 수 있다고 정리합니다.

표로 정리한 내용은 대략 이렇습니다.

잠재 이득                                                                                                                한계

항암제 독성 감소, 내약성 향상	악액질·근손실 악화 가능
자가포식, 당 고갈, IGF-1 감소	사람 대규모 RCT 부족
전임상에서 종양 성장 억제·시너지	단독으로는 관해 유도 근거 약함
FMD(단식 모방 식이)로 실행 가능성 증가	순응도, 저혈당, 전해질, 면역 저하

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근거 수준

전임상(동물·세포)
주기적 단식·FMD가 유방·폐 등 해당과정 의존 종양에서

성장 억제, 항암제 병용 시 종양 축소·생존 연장, 정상조직 보호를 보인 연구가 많습니다.

Longo 계열 FMD(예: ProLon, 5일 750–1100 kcal, 저단백·고지방 식물성)와 케톤식이도

“완전한 단식의 실용적 대안”으로 언급됩니다.

사람 임상
대부분 소규모.

• 항암 전후 24–72시간 단식: 유방암 등에서 오심·피로·점막염·혈액독성 감소 보고.
• 5일 FMD + 항암: 내약성 개선, IGF-1 감소. 종양 축소·생존 연장의 확정 근거는 약함.
• 진행암에서 24시간 단식은 종양 축소 차이는 뚜렷하지 않았고, 피로·컨디션은 나은 편이었다는 보고가 있습니다.

논문 스스로도

“부작용 완화·내약성”에 초점이 맞춰져 있고,

관해·생존을 단식 단독으로 증명하지 못했다고 합니다.

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저자들의 입장

• 단식 = breakthrough로서의 단독 치료 X
• **보조 요법(adjunct)**으로서는 기전이 설득력 있고, 전임상·소규모 임상이 방향은 같다.
• 악액질 환자, 진행암, 영양 예비력이 낮은 환자에게 장기간 물만 마시는 단식은 위험.
• 필요한 것: 암종·병기·환자 상태에 맞춘 대규모 RCT, FMD·면역·표적치료 병용 연구, 의료 감독.

The concept of fasting as a potential cancer treatment has garnered increasing interest, particularly in light of emerging evidence linking dietary interventions to cancer progression and therapy outcomes. This article explores whether fasting, either intermittent or prolonged, can be a viable standalone treatment for cancer or if its therapeutic potential lies in its adjunctive role. Current research suggests that fasting induces a metabolic shift, which may inhibit cancer cell proliferation by depriving them of essential nutrients. Additionally, fasting has been shown to enhance the body's stress resistance, promote autophagy, and possibly make cancer cells more vulnerable to standard treatments such as chemotherapy and radiotherapy. However, the application of fasting as a sole treatment for cancer remains controversial and lacks substantial clinical validation. While animal models and in vitro studies indicate promising results, the translation to human trials is complex, with various types of cancer responding differently to dietary interventions. Moreover, concerns about malnutrition, loss of muscle mass, and the overall health of cancer patients undergoing fasting without supervision must be addressed. The paper critically examines the myth and reality surrounding fasting as a cancer treatment, reviewing key studies and clinical trials to provide a comprehensive understanding of its efficacy and safety. While fasting may hold promise as a supportive therapy, particularly in combination with traditional treatments, there is currently insufficient evidence to support its use as a primary treatment modality. Further research is needed to establish the parameters in which fasting might be beneficial, such as specific cancer types, patient populations, and optimal fasting regimens. Thus, while the idea of fasting as a cancer breakthrough is compelling, it remains a complementary approach rather than a standalone solution in oncology.

단식이 암 치료의 한 방법으로 쓰일 수 있다는 개념은,

식이 개입이 암 진행 및 치료 성적과 연관된다는 최근 근거가 나오면서 관심이 커지고 있다.

본 논문은

간헐적 단식이든 장기간 단식이든,

암이 있는 환자에게 단독 치료로 성립할 수 있는지,

아니면 그 치료적 잠재력이 보조적 역할에 있는지를 검토한다.

현재 연구는 단식이

대사 전환을 유도해 필수 영양소를 제한함으로써

암세포 증식을 억제할 수 있음을 시사한다.

또한 단식은

신체의 스트레스 저항을 높이고, 자가포식(autophagy)을 촉진하며,

항암화학요법·방사선치료 같은 표준 치료에

암세포가 더 취약해지게 만들 수 있다는 점이 보고되어 있다.

그러나

단식을 암의 유일한 치료로 적용하는 것은 여전히 논란이 있으며,

충분한 임상적 검증이 없다.

동물 모델과 시험관 연구는 유망한 결과를 보이지만,

사람 임상으로의 번역은 복잡하고 암종에 따라 식이 개입에 대한 반응이 다르다.

감독 없이 단식을 시행할 경우

영양실조, 근량 감소, 암 환자의 전반적 건강 악화에 대한 우려도 반드시 다루어야 한다.

본 논문은 단식을 암 치료로 보는 주장의 허상과 실상을 비판적으로 검토하고,

주요 연구와 임상시험을 정리해 유효성과 안전성에 대한 종합적 이해를 제공한다.

단식은

특히 기존 치료와 병용할 때 지지 요법으로서 가능성이 있으나,

일차 치료 수단으로 쓰기에는 근거가 부족하다.

어떤 암종, 어떤 환자군, 어떤 단식 프로토콜에서 이득이 있는지를 밝히려면 추가 연구가 필요하다.

따라서

단식이 암 치료의 돌파구라는 생각은 매력적이지만,

현재로서는 종양학에서 단독 해법이 아니라 보완적 접근으로 남아 있다.

단식이 암 치료에서 도움이 될 수 있다고 논문이 정리한 축은 다섯 가지입니다.

1. 항암화학요법 강화
   정상세포는 스트레스 저항 상태로 들어가 항암제 독성이 줄고, 암세포는 더 취약해집니다.
   → *차별적 스트레스 저항(differential stress resistance)*으로 치료 중 암세포를 더 선택적으로 공략할 수 있습니다.
2. 부작용 감소
   항암 중 단기 단식을 한 환자에서 피로, 오심, 위장관 불편이 줄어든다는 연구가 있습니다.
   → 치료 내약성이 좋아져 용량을 높이거나 주기를 더 촘촘히 가져갈 여지가 생깁니다.
3. 자가포식 유도
   손상된 소기관·단백질, 암세포의 기능 저하 미토콘드리아를 치우는 세포 재활용이 켜집니다.
   → 항상성을 돕고, 손상 세포가 증식하기 전에 제거해 종양 성장을 억제할 수 있습니다.
4. 종양 대사 변화
   암세포는 Warburg 효과로 포도당에 의존합니다. 단식은 포도당을 끊고 대사 경로를 흔듭니다.
   → 암세포 증식은 줄고, 정상세포는 케톤·지방산 등 대체 에너지원으로 전환합니다.
5. 면역 반응 강화
   설치류에서 단식 중 NK세포·세포독성 T세포 활성이 증가했습니다.
   → 면역감시가 좋아져 암세포를 찾아 없애는 능력이 올라갈 수 있습니다.

한 줄로 보면, 논문이 말하는 이득은 **“정상세포는 보호하고, 암세포는 당·대사·자가포식·면역 쪽에서 압박한다”**입니다

ERα 양성(호르몬수용체 양성) 유방암에서

주기적 단식이 내분비요법(타목시펜 등)의 효과를 키우는 핵심 이유가

글루코코르티코이드 수용체(GR) 활성화라는 것을

동물·다오믹스·환자 검체로 증명한 논문입니다.

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배경

• HR+ 유방암이 전체의 약 75%. 내분비요법이 주축이지만 내성이 흔함.
• 이전 연구(Caffa et al., Nature 2020)에서 주기적 단식·FMD가 내분비요법 효과를 올리고 내성을 늦춘다는 점은 알려져 있었음.
• 왜 그런지는 불명이었고, 5–10년 매일 먹는 내분비요법과 장기간 단식을 같이 유지하기 어렵다는 현실적 문제도 있었음.
• 이 논문의 목표: 기전을 밝히고, 단식 없이 같은 효과를 내는 약물 전략(스테로이드 보조)이 가능한지 보기.

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핵심 실험 설계

MCF7(사람 ERα+ 유방암) 이종이식 마우스
주 1회 48시간 단식 ± 타목시펜(TMX), 4주 후 종양을
전사체·단백체·면역조직·H3K27ac ChIP-seq·여러 전사인자 ChIP-seq으로 분석.

결과: 단식 단독 < TMX 단독 < 단식+TMX 순으로 종양 억제가 강함(시너지).

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기전 (이 논문의 중심)

1. 에피유전체 재프로그래밍
   TMX+단식 종양에서 활성 인핸서/프로모터 표지 H3K27ac가 크게 바뀜.
2. 켜지는 것: GR, PR
   • 단식 후 GR이 핵으로 이동(활성화의 전형적 소견).
   • GR·PR의 크로마틴 결합이 대규모로 증가.
   • 혈중: 마우스 코르티코스테론·프로게스테론 상승.
   • 사람 FMD 5일 후 코르티솔·프로게스테론 상승.
3. 꺼지는 것: AP-1 (JUN/FOS 계열)
   증식을 돕는 AP-1 부위의 인핸서 활성이 감소. AP-1 자체 결합은 남아 있어도 “일하는 인핸서”가 줄어듦.
4. 인과관계
   • GR knockout → 단식+타목시펜의 항종양 효과가 약해짐.
   • 밖에서 GR 리간드(덱사메타손 등)를 주면 단식 없이도 타목시펜 효과가 커지고 종양이 줄어듦.
     → 단식의 핵심 매개가 내인성 글루코코르티코이드 → GR이라는 뜻.
5. 환자 확인
   주기적 FMD를 한 ERα+ 유방암 환자에서
   • 혈중 코르티솔·프로게스테론 증가
   • FMD 후 종양에서 GR 활성 ↑ ↔ 증식 표지 ↓ (역상관)
     동물 소견과 맞음.

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임상적으로 중요한 메시지

단식이 HR+ 유방암에서 내분비요법을 돕는 이유는
“그냥 당을 끊어서”만이 아니라,
스트레스 호르몬 축(코르티솔/코르티코스테론)이 GR을 켜고, PR도 같이 움직이며, AP-1 증식 프로그램을 눌러서입니다.

저자 제안:
단식·FMD를 오래 못 하는 환자에게

코르티코스테로이드를 내분비요법의 보조제로 시험해 볼 가치가 있다.

주의점:

• 대상은 ERα+ / HR+ 유방암 + 내분비요법 맥락. 모든 암에 일반화하면 안 됨.
• GR은 암종·미세환경에 따라 종양억제일 수도, 면역억제·생존 신호일 수도 있음. 이 논문은 이 세팅에서 종양억제로 읽힘.
• 스테로이드를 바로 임상 표준으로 넣자는 결론이 아니라, 평가할 후보라는 수준.
• FMD/단식은 감독하 주기적 프로토콜. 악액질 환자에게 장기간 물단식을 정당화하는 논문이 아님.

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앞선 Cureus 리뷰와 겹쳐 보면

Cureus 리뷰 (2025)                                                                                      이 Nature 논문 (2025/26)

보조요법은 가능, 단독 치료는 근거 부족	동의. 내분비요법 병용에서 기전을 밝힘
자가포식, Warburg, 차별적 스트레스 저항을 넓게 언급	그 위에 GR/PR 활성화 + AP-1 억제를 전면에
사람 근거가 약하다	FMD 환자 혈청·종양에서 GR–증식 역상관을 제시
FMD를 실용 대안으로 언급	FMD가 코르티솔·프로게스테론을 올린다고 연결

즉 “단식이 암을 고친다”가 아니라,
주기적 에너지 제한 → 내인성 글루코코르티코이드 → GR 프로그램 → 항에스트로겐 효과 증폭
이라는 더 구체적인 축입니다.

Figure 2.

단식이 종양 안 GR·PR 크로마틴 결합을 키우고,

JUN(AP-1) 인핸서 활성은 줄인다

이 그림이 논문의 기전 핵심입니다.

“단식 + 타목시펜”이 왜 더 센지를 수용체 위치 → DNA 결합 → 혈중 호르몬 → 사람 FMD 순으로 보여줍니다.

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a. 면역염색 (ERα / GR / PR)

MCF7 이종이식 종양, 4군: Control · TMX · Fasting · TMX+fasting.

• ERα, PR: 원래부터 핵에 많고, 단식으로 양이나 위치가 크게 안 바뀜.
• GR: 단식 또는 TMX+단식에서 핵 염색이 뚜렷이 증가.
  → 리간드가 붙으면 GR이 핵으로 들어가는 전형적인 활성화 소견.

단식의 첫 가시적 변화는 ERα가 아니라 GR 핵 이동입니다.

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b–c. GR·PR ChIP-seq

히트맵(b)과 평균 신호 곡선(c).

• 단식, 특히 TMX+단식에서 GR이 붙는 부위가 대규모로 늘어남 (왼쪽 빨강, 수천 개 부위).
• PR도 같은 방향으로 결합이 증가 (오른쪽 파랑).
• 피크 중심(0 bp)에서 신호가 가장 높고, 단식군이 Control/TMX만 한 군보다 훨씬 큼.

즉 단식은 GR·PR을 “있게만” 두는 게 아니라 유전체에 실제로 더 많이 앉힌다.

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d–e. JUN (AP-1)과 H3K27ac

증식을 돕는 전사인자 JUN.

• TMX만 쓴 종양에서 활성이 높았던 H3K27ac 부위: JUN 신호가 비교적 유지.
• TMX+단식으로 새로 켜진 H3K27ac 부위: JUN이 거의 안 붙음 (e 오른쪽, 곡선이 납작).
• 단식이 AP-1을 DNA에서 완전히 떼는 것이 아니라, 새로 생기는 인핸서는 GR/PR 자리이고 AP-1 자리는 아님.
  기존 AP-1 인핸서의 “일”은 줄어듦.

정리: 켜짐 = GR/PR, 증식 인핸서 쪽 AP-1 활동은 상대적 약화.

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f–g. 마우스 혈중 호르몬

주 1회 48시간 단식 × 4사이클, TMX+단식 전후 채혈.

• 코르티코스테론(마우스 주 글루코코르티코이드): Pre → Post로 뚜렷 상승 (P = 0.0013).
• 프로게스테론: 역시 상승 (P = 0.0039).

종양 안 GR 핵 이동·ChIP 증가의 리간드 공급원이 단식이 올린 내인성 스테로이드임을 보여줍니다.

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h–j. 사람: 내분비요법 중인 유방암 + 5일 FMD

두 임상 코호트 (NCT05748704, NCT03454282).

• 5일 FMD 후 코르티솔 상승 (i: P = 0.003; j: P = 1.7×10⁻⁸).
• 프로게스테론도 평균적으로 오름 (P = 0.048). 개인차는 있음.

마우스 코르티코스테론 소견이 사람 코르티솔로 재현됩니다.

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한 줄 해석

단식(또는 FMD)
→ 혈중 코르티솔/코르티코스테론·프로게스테론 ↑
→ 종양 GR(및 PR) 핵 이동·유전체 결합 ↑
→ AP-1(JUN) 증식 인핸서 활성은 상대적으로 ↓
→ 타목시펜의 항종양 효과가 커짐.

앞 그림(Fig. 1)이 “에피유전체가 바뀐다”였다면,

Fig. 2는 그 변화의 주인공이 GR이고, 사람 FMD에서도 같은 호르몬 축이 움직인다는 증거입니다

이 그림 = GR이 ‘필요한지’, 덱사메타손이 단식을 대신할 수 있는지

Fig. 2가 “단식 → 호르몬 ↑ → GR이 DNA에 붙는다”였다면, 이 그림은 인과관계와 약물 대체입니다.

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a–b. GR을 없애면 단식+타목시펜 시너지가 사라짐

왼쪽: MCF7 NT(대조, GR 정상)
오른쪽: MCF7 GR-KO(GR 제거)

• GR이 있을 때: 단식(빨강) < TMX(파랑) < TMX+단식(초록) 순으로 종양이 가장 많이 줄어듦 (P = 0.01, 0.0004).
• GR이 없으면: 세 곡선이 겹침. TMX+단식이 TMX만보다 낫지 않음 (P = 0.96, 0.22).

b 막대그래프(종료 시점):
TMX+단식에서만 NT(회색, 거의 0에 가깝게 억제) vs GR-KO(노랑, 억제 실패) 차이가 뚜렷 (P = 0.0027).

해석: 단식이 타목시펜을 강화하려면 종양 세포 GR이 필수. 당 고갈만으로 설명되지 않습니다.

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c–e. 단식 대신 덱사메타손(Dexa, GR 리간드)

c: 단식 주기에 맞춰 TMX + Dexa를 펄스로 줌.

d: 종양 부피
Control이 제일 크고, 단식·TMX·Dexa 단독은 중간,
TMX+단식과 TMX+Dexa가 가장 낮음 (P = 0.04, 0.02).
→ Dexa가 단식의 항종양 시너지를 흉내 냄(phenocopy).

e: 다른 실험에서도 TMX+Dexa가 TMX 또는 Dexa 단독보다 억제가 강함.

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f–g. 약을 끊은 뒤에도 효과가 남는지

점선 이전 = 치료, 이후 = 관찰만.

• Control·TMX는 치료를 멈춰도 곧 다시 자람.
• TMX+Dexa는 성장이 더 늦게 재개되고, 생존이 김 (P = 0.0044).

단식을 매일 할 수 없어도, GR을 약으로 켜면 내분비요법 효과가 연장될 수 있다는 전임상 근거입니다. 사람 표준 치료로 바로 옮기자는 데이터는 아닙니다.

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h. 모식도 (논문이 말하는 모델)

왼쪽, TMX만

• 종양촉진 부위: ERα + AP-1이 인핸서(H3K27ac)를 유지 → 증식·진행 유전자 ON.
• 종양억제 부위: ERα만으로는 GR/PR 프로그램이 약함.

오른쪽, TMX + 단식

• 코르티솔·프로게스테론 증가.
• GR·PR이 억제 부위에 결합 → 유방암 성장 억제 유전자 ON.
• 촉진 부위에서 AP-1 인핸서 활성은 상대적으로 약해짐.

한 줄:
단식 = 내인성 글루코코르티코이드로 GR을 켜는 스위치.
GR이 없으면 스위치가 고장 나고, Dexa로 GR을 직접 켜면 단식과 비슷한 시너지가 납니다.

임상으로 옮길 때의 조건은 그대로입니다. ERα+ / 내분비요법 맥락, 감독하 주기적 FMD 또는 (향후 시험할) 스테로이드 보조. 악액질 환자의 장기간 물단식이나 모든 암종 일반화는 이 그림이 말하지 않습니다.

Introduction and background

Cancer is one of the most dreadful diseases in the world, causing a whooping increase in morbidity and mortality worldwide regardless of intense human development. It is characterized by the uncontrolled growth of aberrant cells, afflicting 19.3 million people and causing almost 10 million people deaths globally in 2024 [1]. The concept of fasting as a cancer treatment has sparked significant debate and intrigue in both the medical community and the general public. Fasting, an ancient practice often associated with religious or cultural traditions, has gained renewed attention in recent years due to its potential therapeutic benefits in modern medicine, particularly oncology. The underlying hypothesis is that fasting alters the body's metabolic state, creating conditions that may inhibit cancer growth and enhance the efficacy of conventional treatments [2]. Proponents of fasting argue that it can induce autophagy, a process where the body clears damaged cells and regenerates healthier ones, and that it may make cancer cells more vulnerable to treatment by depriving them of glucose and other essential nutrients needed for rapid proliferation [2]. In addition, fasting is believed to trigger a stress-resistant state in normal cells, offering protection against the toxic side effects of chemotherapy and radiotherapy, while selectively targeting cancer cells, which are less adaptable to nutrient scarcity [3]. These concepts are grounded in research that shows how cancer cells exhibit altered metabolism, often referred to as the "Warburg effect," where they preferentially rely on glycolysis for energy even in the presence of oxygen. By restricting glucose availability through fasting, it is thought that the growth of cancer cells may be slowed or halted [4].

Despite the intriguing scientific basis, the idea of using fasting as a primary treatment for cancer remains controversial. Much of the current evidence supporting fasting’s anti-cancer effects comes from animal studies and in vitro experiments, with limited large-scale human trials to corroborate these findings. In rodent models, fasting has shown promise in reducing tumor growth, improving the effectiveness of chemotherapy, and enhancing overall survival [5]. However, translating these results to humans is complex due to differences in physiology, tumor types, and individual patient health statuses. While some small clinical trials have suggested that short-term fasting or fasting-mimicking diets may improve patients' tolerance to chemotherapy and reduce side effects, the long-term safety and efficacy of such interventions in treating cancer remain uncertain [6]. Furthermore, the type of fasting regimen whether intermittent fasting, prolonged fasting, or calorie restriction adds another layer of complexity to the discussion, as different cancers and patients may respond differently to various fasting protocols.

Another concern with fasting as a cancer treatment is its potential for malnutrition, particularly in cancer patients who are already at risk of weight loss and muscle wasting due to their disease. Cancer cachexia, a syndrome characterized by severe muscle loss and fat depletion, affects many cancer patients and can significantly impact treatment outcomes and quality of life [7]. Fasting, if not carefully managed, could exacerbate these issues, leading to weakened immune function, reduced tolerance to treatment, and overall poorer prognosis. For these reasons, many oncologists are cautious about recommending fasting as a therapeutic strategy, particularly outside of controlled clinical settings. While the idea of fasting as a cancer treatment is compelling and has generated considerable interest, it remains largely experimental at this stage [7]. The potential benefits of fasting, especially as an adjunct to conventional therapies, are worthy of further exploration, but there is insufficient evidence to support its use as a standalone treatment. More robust clinical trials are needed to determine the efficacy, safety, and optimal conditions under which fasting might be beneficial in cancer care. In this review, we will explore the myths and breakthrough of fasting in cancer treatment.

Review

Mechanistic insights: fasting affects cancer cells

Fasting has been studied as a potential therapeutic approach for cancer due to its profound effects on cellular metabolism in cancer and the rest of the diseases, which may inhibit cancer cell growth and enhance the effectiveness of traditional treatments. The mechanisms behind fasting suggest that it induces a metabolic shift, altering both the behavior of cancer cells and the body’s overall response to cancer therapy. Autophagy not only helps in cleaning dysfunctional cells but also promotes cellular repair and regeneration, contributing to a healthier cellular environment in the body (Table 1).

Table 1. Intricate details on fasting's role in oncology, its mechanisms, limitations, and future potential, aligning with advanced scientific discourse.

Sources: Refs

Aspect	Details	Scientific Implications
Potential Benefits
Enhances Chemotherapy	Fasting induces a stress-resistant state in normal cells, reducing chemotherapy toxicity, while cancer cells become more vulnerable.	Improves differential stress resistance, allowing more effective targeting of cancer cells during treatment [11].
Reduces Side Effects	Studies show reduced fatigue, nausea, and gastrointestinal discomfort in patients undergoing short-term fasting during chemotherapy.	Enhances patient tolerance to treatment, potentially allowing higher or more frequent treatment doses [3].
Induces Autophagy	Fasting triggers cellular recycling mechanisms that clear damaged organelles and proteins, including dysfunctional mitochondria in cancer cells.	Promotes cell homeostasis and may inhibit tumor growth by eliminating damaged cells before they proliferate [8,9].
Modifies Tumor Metabolism	Cancer cells depend on glucose for survival (Warburg effect). Fasting deprives them of glucose, disrupting their metabolic pathways.	Glucose deprivation reduces cancer cell proliferation while normal cells adapt to alternative energy sources [8].
Boosts Immune Response	Rodent studies show increased activity of natural killer (NK) cells and cytotoxic T cells during fasting.	Enhanced immune surveillance improves the body’s natural ability to identify and destroy cancer cells [21,22].
Challenges and Limitations
Malnutrition Risk	Cancer patients often experience cachexia or severe weight loss; fasting may exacerbate this condition.	Increases the risk of complications such as muscle wasting and weakened immune function [23].
Limited Human Data	Most evidence comes from preclinical animal studies and small-scale human trials.	Insufficient large-scale clinical trials to establish fasting as a standardized therapy [30].
Not a Standalone Therapy	Fasting alone is unlikely to induce tumor remission; it may only complement conventional treatments like chemotherapy and radiation.	Requires integration with existing treatment protocols and ongoing medical supervision [30].
Adherence Challenges	Patients may struggle to maintain fasting regimens due to hunger, fatigue, or existing health conditions.	Practicality issues limit its widespread implementation in clinical oncology [31].
Potential Adverse Effects	Extended fasting could lead to electrolyte imbalances, hypoglycemia, and weakened immunity.	Increased risk of complications, especially in already fragile cancer patients [23].
Future Directions
Clinical Trials	Larger, randomized controlled trials are needed to validate fasting’s safety and efficacy as a complementary therapy.	This could provide robust evidence to support the use of fasting in oncology [31].
Personalized Approaches	Fasting regimens may need to be tailored to individual patient profiles, including cancer type, stage, and overall health.	Precision oncology could integrate fasting as part of a multidisciplinary approach to treatment [33].
Combination Strategies	Exploring fasting in combination with immunotherapies, targeted therapies, or fasting-mimicking diets.	Synergistic effects could amplify treatment outcomes while minimizing side effects [34].

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Role of autophagy

Autophagy is crucial in maintaining cellular homeostasis by breaking down and recycling damaged organelles, proteins, and other cellular debris. In fasting, autophagy is unregulated as the body shifts its focus from an anabolic, the building state of the body, to a catabolic, the breakdown state of the body, utilizing the internal resources for energy. This self-digestive process (autophagy) is particularly important in clearing cancerous cells that are more susceptible to damage and dysfunction when compared to normal cells. Cancer cells, typically having higher rates of growth and proliferation, accumulate a significant amount of metabolic waste and damaged cellular components. Further, by enhancing autophagy through fasting, the body may effectively clear out all the damaged cells, reducing tumor growth [8].

Fasting triggers a unique stress response in normal cells, making them more resistant to the harmful effects of radiotherapy and chemotherapy. While cancerous cells are highly sensitive to nutrient availability, normal cells can enter a protective state during fasting, reducing their metabolic activity and enhancing their ability to withstand environmental stressors. Moreover, this selective protection of normal cells is one of the key benefits of fasting, as it could potentially reduce the side effects of cancer treatments while allowing the treatments to more effectively target cancer cells [8,9].

The Warburg effect: impact on cancer cell metabolism

The Warburg effect is yet another important mechanism through which fasting may impact cancer cells by targeting their altered metabolic pathways. Cancer cells exhibit a phenomenon commonly known as the Warburg effect, where they truly rely on glycolysis for energy production, even in the presence of oxygen [10]. This metabolic reprogramming permits cancer cells to generate energy rapidly, which is important to sustain their rapid growth and proliferation. However, this dependence on glycolysis also makes cancer cells more vulnerable to changes in nutrient availability, particularly in the availability of glucose. In fasting, the body’s glucose levels decrease, directly forcing cells to rely on alternative sources of energy, such as fatty acids and ketone bodies. Normal cells can efficiently switch to these alternative metabolic pathways, but cancer cells, due to their reliance on glycolysis, struggle to adapt [10]. This metabolic vulnerability creates an opportunity for fasting to suppress cancer cell growth by depriving them of the glucose they need for survival and proliferation. Studies have shown that fasting can reduce glucose and insulin-like growth factor 1 (IGF-1) levels, both of which are critical for cancer cell metabolism and growth. Lower levels of IGF-1, in particular, have been associated with reduced tumor growth and improved responses to chemotherapy [10].

Enhancing chemotherapy and radiotherapy

Fasting also enhances the effectiveness of conventional cancer treatments such as chemotherapy and radiotherapy by sensitizing cancer cells to these therapies. As fasting induces metabolic stress in cancer cells, it compromises their ability to repair DNA damage, making them more susceptible to the effects of chemotherapy and radiation. Radiotherapy and chemotherapy work by inducing DNA damage in rapidly dividing cells, and cancer cells, with their already impaired metabolic and repair mechanisms, are less able to recover from such damage during periods of fasting [11]. Furthermore, fasting induces a shift in the immune system that may further promote anti-cancer activity. In fasting, the production of pro-inflammatory cytokines decreases, and the immune system becomes more efficient at identifying and destroying cancer cells. Fasting may enhance the activity of natural killer (NK) cells, which play a key role in immune surveillance and tumor destruction. This immune-modulatory effect provides an additional mechanism through which fasting aids in cancer treatment, by both directly inhibiting tumor growth and improving the body's natural defense system against cancer [11].

Stress resistance in normal cells

While fasting increases the vulnerability of cancer cells to treatment, it simultaneously creates a protective, stress-resistant state in normal cells. This dual action, making cancer cells more susceptible to damage while protecting healthy cells, has significant implications for cancer therapy. Fasting decreases the growth signals in normal cells, effectively slowing down their metabolic processes and reducing the likelihood of damage from chemotherapy and radiotherapy. This stress-resistant state may allow for higher doses or more aggressive treatment regimens without increasing toxicity to the patient.

Research studies have shown that normal cells can enter a phase of maintenance during fasting time, where they conserve energy and resources, allowing them to recover more easily from treatment-induced stress [12]. Moreover, the cancerous cells, which are unable to slow down their growth pattern, continue to divide and divide and thus become more exposed to the cytotoxic effects of treatments. This differential response between normal cells and cancerous cells is one of the most promising aspects of integrating fasting into cancer therapy, as it could lead to more effective treatments with fewer side effects [13]. The mechanistic insights that are followed in the fasting regime as a treatment for cancer reveal a complex interplay between metabolism, cellular stress responses, and immune function. Fasting induces autophagy by enhancing the immune activity and creating a metabolic environment, inhibiting the growth of cancer cells while protecting normal cells. These processes make fasting a very compelling complementary therapy in oncology, particularly in combination with chemotherapy and radiotherapy [14]. However, while many preclinical studies and clinical trials suggest promising outcomes of this fasting, further research is needed to fully understand the long-term mechanism and safety of fasting as part of a cancer treatment regimen. Fasting may not be the only solution, but its ability to exploit the metabolic vulnerabilities of cancer cells while safeguarding normal cells presents a unique opportunity to improve cancer treatment outcomes.

Evidence from animal models and in vitro studies

Fasting has been extensively studied in cancer, particularly in animal models, to understand its exact potential effects on cancer progression and in its treatment. These studies have shown promising results, indicating that fasting could reduce tumor growth cells, by enhancing the sensitivity of cancer cells to chemotherapy and radiation, and even improve the survival rates in rodents. The compelling evidence that came out from these studies has laid the foundation for exploring fasting as an adjunctive strategy in cancer therapy, although translating these findings to human clinical practice remains a challenge [15,16].

Tumor growth reduction

Fasting has been shown to play a significant role in reducing tumor growth, primarily through metabolic adaptations that deprive cancer cells of the nutrients required for their rapid proliferation. Animal model studies have demonstrated that fasting triggers systemic changes, including reduced glucose availability and altered insulin and IGF-1 signaling, which can restrict the energy supply to tumor cells, thereby inhibiting their progression [16]. A notable study in mice with various tumor types found that periodic fasting cycles significantly slowed tumor growth rates. This effect was particularly pronounced in highly glycolytic cancers, such as breast and lung tumors, which rely heavily on glucose metabolism for survival [16]. By lowering circulating glucose and insulin levels, fasting disrupts the metabolic pathways essential for these tumors, thereby suppressing their growth. Additionally, fasting has been found to enhance the effectiveness of conventional cancer therapies. The same study observed that, when fasting was combined with chemotherapy, the reduction in tumor size was significantly greater compared to chemotherapy alone [17]. This suggests that fasting creates a metabolic environment that not only inhibits tumor progression but also increases cancer cell sensitivity to therapeutic interventions. One proposed mechanism is that fasting promotes differential stress resistance, where healthy cells enter a protective state under nutrient deprivation, while cancer cells, which lack this adaptive ability, become more vulnerable to treatment-induced damage. These findings highlight the potential of fasting as a complementary strategy in oncology, offering a non-invasive approach to slowing tumor growth and enhancing treatment efficacy. Clinical research is needed in the future to determine optimal fasting protocols and to explore their integration into standard cancer treatment regimens [17].

Fasting-induced synergistic effects on cancer therapies

Preclinical studies have shown that fasting elevates the sensitivity of cancer cells to chemotherapy and radiation therapy, making these treatments more effective [18]. Chemotherapy and radiation work by causing damage to rapidly dividing cells, which include both cancer cells and, to a lesser extent, normal cells. Moreover, fasting appears to differentially protect normal cells while making cancer cells more vulnerable to these therapies. The underlying mechanism behind this enhanced sensitivity is linked to metabolic stress; that is, fasting imposes on cancer cells. Further, the cancer cells, already under metabolic strain due to their rapid growth, struggle to cope with the additional stress of nutrient deprivation caused by fasting. As a result, they become more susceptible to the DNA damage caused by chemotherapy and radiation therapy [19]. In contrast, normal cells begin to enter a stress-resistant state by fasting, slowing down their metabolic activity, and making them less vulnerable to treatment-induced damage. This phenomenon is termed differential stress resistance and stands as a key advantage of fasting in cancer therapy, as it allows for more aggressive treatment without elevating the toxicity to healthy cells. In a notable rodent study, researchers found that short-term fasting before chemotherapy led to a dramatic improvement in treatment efficacy [19]. Mice that underwent fasting before receiving chemotherapy experienced greater tumor shrinkage and prolonged survival compared to those that were fed normally. Importantly, fasting also reduces the toxic side effects of chemotherapy, such as weight loss and damage to the gastrointestinal tract, which are common concerns in cancer treatment. These findings highlight the potential of fasting to not only enhance the effectiveness of chemotherapy but also improve the overall well-being of patients during treatment [20].

Cellular recycling and immune system regulation in cancer

Fasting-induced autophagy, the process by which cells break down and recycle damaged components, is another critical mechanism that contributes to its anti-cancer effects. Autophagy is upregulated during fasting, allowing the body to clear out dysfunctional or cancerous cells while promoting the regeneration of healthier ones. In animal models, fasting has been shown to increase autophagic activity in tumors, leading to a reduction in tumor size and a delay in cancer progression [21]. In addition to promoting autophagy, fasting appears to modulate the immune system, enhancing the body's natural ability to fight cancer. Studies in rodents have demonstrated that fasting can boost the activity of immune cells, particularly NK cells and cytotoxic T cells, which are responsible for identifying and destroying cancer cells [21]. In one study, fasting was found to increase the infiltration of NK cells into tumors, leading to a more robust immune response against cancer. This immune modulation could provide an additional layer of protection against cancer, complementing the direct anti-tumor effects of fasting [22].

Fasting-mimicking diets (FMDs) and caloric restriction

Beyond complete fasting, FMDs and caloric restriction have also been explored in preclinical studies as less extreme but potentially effective alternatives. FMDs are designed to replicate the metabolic effects of fasting without requiring total abstinence from food. In rodent models, FMDs have shown similar benefits to fasting, including reduced tumor growth, increased chemotherapy efficacy, and improved survival rates. These diets may offer a more practical approach to incorporating fasting-like interventions into cancer treatment, particularly for patients who may not tolerate prolonged fasting [23].

Examples of FMDs

ProLon diet: A commercially available five-day plant-based diet developed by Dr. Valter Longo. It provides around 750-1100 kcal per day, with a composition rich in healthy fats, moderate carbohydrates, and minimal protein to mimic fasting effects.

Ketogenic diet: A high-fat, low-carbohydrate diet that induces a fasting-like metabolic state by promoting ketone body production, leading to cellular stress resistance and potential anti-cancer effects.

These diets offer a more feasible alternative to prolonged fasting while retaining many of its therapeutic benefits, including improved metabolic health and enhanced response to cancer therapies.

Caloric restriction, which involves reducing overall calorie intake without fasting completely, has also been studied in animal models of cancer. Like fasting, caloric restriction has been shown to inhibit cancer cell growth and enhance treatment efficacy. However, the degree of benefit appears to vary depending on the type of cancer and the specific caloric restriction protocol used. Preclinical studies in animal models and in vitro experiments provide strong evidence that fasting can reduce tumor growth, increase the sensitivity of cancer cells to chemotherapy and radiation, and improve survival rates [23]. The metabolic stress imposed by fasting deprives cancer cells of essential nutrients, while normal cells enter a protective state, reducing the side effects of treatment. Fasting’s anti-cancer potential is further strengthened by its role in cellular recycling and immune system regulation. While current findings are encouraging, further research is essential to translate these benefits into clinical oncology. More human trials are necessary to eval‎uate the safety, effectiveness, and practical application of fasting and FMDs across various cancer types and patient populations. Despite these challenges, preclinical studies indicate that fasting could serve as a valuable adjunct to conventional cancer treatments [24].

Short-term fasting and chemotherapy tolerance

A number of small-scale clinical studies have explored the impact of short-term fasting (typically 24-72 hours) on cancer patients undergoing chemotherapy. These studies have sought to determine whether fasting can reduce the toxicity associated with chemotherapy, such as fatigue, nausea, and gastrointestinal discomfort, while improving the body’s response to treatment. One of the key findings from these trials is that short-term fasting may indeed improve patients' tolerance to chemotherapy. In a study involving breast cancer patients, those who fasted for 48 hours before and after chemotherapy reported fewer side effects compared to those who followed a normal diet. Patients who fasted experienced less nausea, fatigue, and weakness, common side effects of chemotherapy [25]. Moreover, some studies suggest that fasting may protect healthy cells from the damaging effects of chemotherapy, a phenomenon known as "differential stress resistance." Fasting induces a metabolic shift in normal cells that allows them to enter a stress-resistant state, reducing the collateral damage caused by chemotherapy while leaving cancer cells more vulnerable [26]. In a separate trial involving patients with a variety of cancer types, fasting for up to 72 hours was associated with a reduction in chemotherapy-induced side effects, such as mucositis (inflammation of the digestive tract lining) and hematologic toxicity (damage to blood cells). While these findings are encouraging, they are based on relatively small sample sizes and require further validation through larger, more rigorous studies [27].

Nutritional strategies imitating fasting: a practical approach

FMDs are designed to replicate the metabolic effects of fasting without requiring patients to completely abstain from food. These diets typically involve low-calorie, low-protein, high-fat meals that simulate a fasting state by reducing glucose and insulin-like IGF-1 levels. FMDs have been proposed as a more practical alternative to complete fasting, particularly for cancer patients who may be unable to tolerate prolonged periods without food due to malnutrition or other health concerns [28]. Several early-phase clinical trials have investigated the potential benefits of FMDs in cancer therapy. In a pilot study conducted on patients with breast cancer, those who followed a five-day FMD during chemotherapy cycles showed improved tolerance to treatment, reporting fewer side effects, such as fatigue, nausea, and dizziness. Moreover, markers of cellular stress, such as IGF-1, were reduced in the FMD group, suggesting that the diet may create a less favorable environment for cancer cell proliferation. While these results are promising, the study was small, and additional research is needed to confirm‎ these findings in larger patient populations [28]. Although some clinical trials have demonstrated that fasting can improve patients' quality of life during cancer treatment, its direct impact on tumor reduction and survival rates remains uncertain. The majority of studies have focused on fasting's ability to mitigate side effects and improve treatment tolerability rather than on fasting as a standalone intervention to shrink tumors or improve overall survival outcomes. In one of the few trials examining the effects of fasting on cancer outcomes, patients with advanced cancer who fasted for 24 hours before and after chemotherapy did not experience significant tumor shrinkage compared to those who did not fast [20]. However, fasting appeared to have a positive effect on patients' overall well-being, with many reporting improved energy levels and reduced treatment-related fatigue. Importantly, fasting did not appear to compromise the effectiveness of chemotherapy, suggesting that it may be a safe adjunct to conventional treatment regimens. However, larger, long-term studies are needed to determine whether fasting can directly influence cancer progression and survival rates in humans [20].

Obstacles and considerations in clinical research

Several challenges have limited the widespread adoption of fasting in clinical oncology. One of the primary concerns is the potential for fasting to exacerbate malnutrition in cancer patients, many of whom are already at risk of weight loss and muscle wasting due to their disease. Prolonged fasting could lead to further nutritional deficits, particularly in patients with advanced cancer, who may have limited reserves of energy. To mitigate these risks, most clinical trials have focused on short-term fasting or FMDs, which are less likely to cause severe malnutrition [23]. Another limitation is the small sample size of many human trials on fasting and cancer. Most studies to date have involved fewer than 100 participants, making it difficult to draw definitive conclusions about the safety and efficacy of fasting in larger, more diverse patient populations. Furthermore, the heterogeneity of cancer types and treatment regimens in these trials makes it challenging to generalize the findings to all cancer patients. Future studies will need to address these limitations by recruiting larger cohorts and exploring the effects of fasting in specific cancer subtypes, such as breast, lung, or colorectal cancer. While small-scale clinical studies suggest that short-term fasting or FMDs may help cancer patients tolerate chemotherapy better and experience fewer treatment-related side effects, the evidence supporting fasting’s direct impact on cancer outcomes, such as tumor reduction and survival rates, remains limited [23]. Current clinical trials have primarily focused on fasting as an adjunct therapy rather than a primary treatment, and more research is needed to establish its safety and efficacy in larger, more rigorous studies [29]. For now, fasting shows promise as a complementary approach in cancer care, but it is not yet robust enough to be considered a standalone treatment.

A supportive therapeutic approach

Fasting has emerged as a potential complementary therapy in the treatment of cancer, offering a way to enhance the efficacy of traditional treatments, such as chemotherapy and radiation. While fasting is not a standalone cure for cancer, research suggests that it may help mitigate some of the adverse side effects associated with conventional cancer therapies, making them more tolerable for patients. This, in turn, could lead to better overall outcomes by allowing for higher doses or more frequent treatment cycles without compromising patient health. As such, fasting is increasingly being explored as an adjunctive measure to improve patient quality of life and potentially enhance treatment efficacy [30].

Minimizing therapy-induced adverse effects

Chemotherapy and radiation are effective cancer treatments but come with significant side effects, including nausea, fatigue, and gastrointestinal issues, which can diminish patients’ quality of life and limit the intensity or frequency of treatment. Some studies have shown that fasting or FMDs can alleviate these side effects, offering a reprieve for patients undergoing aggressive treatment. The mechanism behind this benefit is thought to be linked to the body’s response to nutrient deprivation [30]. Fasting triggers a protective, stress-resistant state in normal cells, which makes them less vulnerable to the damaging effects of chemotherapy and radiation. This phenomenon, known as “differential stress resistance,” may allow normal cells to better withstand treatment while leaving cancer cells more susceptible to damage. For instance, in several small-scale human trials, patients who fasted before and after chemotherapy reported fewer side effects such as fatigue, nausea, and diarrhea. By reducing these debilitating side effects, fasting could help patients tolerate more intensive treatment schedules, which might improve cancer outcomes by allowing for more aggressive treatment strategies [30].

Boosting cancer treatment outcomes with metabolic interventions

Fasting may not only reduce the side effects of chemotherapy and radiation but also improve their effectiveness. Cancer cells are known for their rapid growth and high metabolic demand, particularly their reliance on glucose as an energy source (a process known as the Warburg effect). Fasting deprives cancer cells of glucose, creating a metabolic environment that is unfavorable for their survival. While normal cells can switch to alternative energy sources during fasting, cancer cells are less adaptable, making them more vulnerable to the effects of nutrient deprivation [31]. This metabolic stress could enhance the ability of chemotherapy and radiation to kill cancer cells more effectively. Moreover, some studies suggest that fasting may increase the sensitivity of cancer cells to treatment. For instance, in rodent models, fasting has been shown to boost the efficacy of chemotherapy by making cancer cells more vulnerable to the DNA damage induced by treatment [31]. Although more clinical research is needed to confirm‎ these findings in humans, the preliminary data are promising, particularly for cancers that are highly dependent on glucose metabolism.

Integrating fasting into cancer care: precautions and clinical guidance

While fasting shows promise as a complementary therapy, it is not without risks. Cancer patients are often in a weakened state and may already be experiencing malnutrition due to their illness and treatment. Prolonged fasting could exacerbate these conditions, leading to weight loss, muscle wasting, and a weakened immune system [32]. As such, fasting should always be done under medical supervision, especially for cancer patients. These diets have shown similar benefits in reducing chemotherapy side effects and enhancing treatment efficacy while being easier to implement, particularly for patients who cannot tolerate long periods without food [32]. While fasting should not be viewed as a cure for cancer, it may help patients better tolerate conventional treatments, thereby improving overall outcomes. However, fasting, particularly in cancer patients, should be approached cautiously and under the guidance of medical professionals to avoid exacerbating malnutrition or other health risks [33]. As research into fasting and FMDs continues, it may become an important tool in the oncology toolkit, improving both patient experience and treatment success [33].

Apoptosis and its role in fasting-induced cancer modulation

Apoptosis, a highly regulated form of programmed cell death, plays a crucial role in maintaining cellular homeostasis and eliminating damaged or cancerous cells. Emerging evidence suggests that fasting may enhance apoptotic pathways, thereby contributing to cancer suppression. Several studies indicate that fasting modulates key apoptotic signaling pathways, including the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) pathways, ultimately leading to tumor cell elimination [34]. Additionally, fasting-induced metabolic stress triggers pro-apoptotic proteins such as p53, BAX, and caspase activation while downregulating anti-apoptotic factors such as Bcl-2, thereby sensitizing cancer cells to apoptosis. This mechanism is further supported by a recent review highlighting fasting as a potential adjunct therapy in oncology, where apoptosis is a key driver of its therapeutic benefits [32]. Given these findings, a deeper exploration of apoptosis within the context of fasting would provide a more comprehensive understanding of its implications in cancer treatment, particularly in combination with conventional therapies [32].

Conclusions

In conclusion, fasting as a cancer treatment holds significant potential, particularly as an adjunctive therapy to enhance the efficacy of traditional cancer treatments. The mechanisms by which fasting may impact cancer progression - such as autophagy, metabolic regulation, and stress resistance - are compelling. However, the lack of large-scale human trials and the potential risks of malnutrition make fasting a complementary approach rather than a primary treatment strategy. Further research is needed to fully understand the therapeutic potential of fasting in oncology and to identify the patient populations and cancer types that might benefit the most. Until more conclusive evidence emerges, fasting should be approached cautiously, with careful oversight by healthcare professionals to ensure patient safety and avoid adverse effects.

Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Author Contributions

Concept and design:  Ghizal Fatima, Abbas A. Mehdi, Jan Fedacko, Najah Hadi, Aminat Magomedova, Ammar Mehdi

Acquisition, analysis, or interpretation of data:  Ghizal Fatima, Abbas A. Mehdi, Jan Fedacko, Najah Hadi, Aminat Magomedova, Ammar Mehdi

Drafting of the manuscript:  Ghizal Fatima, Abbas A. Mehdi, Jan Fedacko, Najah Hadi, Aminat Magomedova, Ammar Mehdi

Critical review of the manuscript for important intellectual content:  Ghizal Fatima, Abbas A. Mehdi, Jan Fedacko, Najah Hadi, Aminat Magomedova, Ammar Mehdi

Supervision:  Ghizal Fatima

References