Abstract
Radiotherapy has an established role in the clinical treatment of patients with a variety of cancers owing to the ability to preferentially kill malignant cells mostly while sparing their non-malignant counterparts. Results from phase I–II trials also suggest that radiotherapy can have therapeutically relevant immunostimulatory effects, especially when combined with immune-checkpoint inhibitors. Over the past two decades, evidence has emerged showing that intestinal microbial communities have a major influence on the immunological tonus of patients with cancer and can influence sensitivity to various immunotherapies, including immune-checkpoint inhibitors and chimeric antigen receptor T cells. Here, we critically discuss the effects of such microbial ecosystems on radiotherapy-induced toxicities and tumour-targeting immune responses, with a focus on the clinical potential of these relationships for predictive and therapeutic clinical applications.
Key points
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Both the intestinal and intratumoural microbiota have emerged as regulators of innate and adaptive antitumour immunity during disease progression and in response to radiotherapy.
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The composition of microbial ecosystems populating mucosae and their interactions with epithelial membranes influence the severity of radiotherapy-induced mucositis.
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Intestinal irradiation has metabolic and immunological effects with systemic outreach that can either suppress or promote cancer immunosurveillance, depending on the irradiated organ, radiotherapy dose and target volume as well as the microbiota composition at baseline.
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Carefully designed microbiota-centred interventions provide promising methods of promoting radiotherapy-induced antitumour immunity while alleviating treatment-associated toxicities.
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Acknowledgements
The authors would like to thank long-standing collaborations with the Histopathology Department of Gustave Roussy, the Experimental and Translational Pathology (PETRA, AMMICA, INSERM US23/CNRS) Platform at Gustave Roussy, and the Bioinformatics Platform at Gustave Roussy. The work of J.C. is supported by the ARC foundation, the National Natural Science Foundation of China (82173079), the Natural Science Foundation of Guangdong Province of China (2022A1515011220) and GuangDong Basic and Applied Basic Research Foundation-Enterprise Joint Funds (2022A1515220007 and 2024A1515220093, PI: C. Chen). The work of E.D. is supported by F. Hoffmann-La Roche, French National Research Agency under the France 2030 investment plan (grant application N° ANR-21-RHUS-0005) and the imCORE research network (N°SG40863). The work of G.K. is supported by the Ligue contre le Cancer (équipe labellisée), Agence National de la Recherche (ANR-22-CE14-0066 VIVORUSH, ANR-23-CE44-0030 COPPERMAC, ANR-23-R4HC-0006 Ener-LIGHT), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Fondation pour la Recherche Médicale (FRM), European Research Council Advanced Investigator Award (ERC-2021-ADG, Grant No. 101052444; project acronym: ICD-Cancer, project title: Immunogenic cell death (ICD) in the cancer-immune dialogue), the ERA4 Health Cardinoff Grant Ener-LIGHT, European Union Horizon 2020 research and innovation programmes Oncobiome (grant agreement number: 825410, Project Acronym: ONCOBIOME, Project title: Gut OncoMicrobiome Signatures [GOMS] associated with cancer incidence, prognosis and prediction of treatment response), Prevalung (grant agreement number 101095604, Project Acronym: PREVALUNG EU, project title: Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception), national support managed by the Agence Nationale de la Recherche under the France 2030 programme (reference number 21-ESRE-0028, ESR/Equipex + Onco-Pheno-Screen), Hevolution Network on Senescence in Aging (reference HF-E Einstein Network), Institut National du Cancer (INCa), Institut Universitaire de France, PAIR-Obésité INCa_1873, the RHUs Immunolife and LUCA-pi (ANR-21-RHUS-0017 and ANR-23-RHUS-0010, both dedicated to France Relance 2030), Seerave Foundation, and SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by INCa, Ministère des Solidarités et de la Santé and INSERM). This study contributes to the IdEx Université de Paris Cité ANR-18-IDEX-0001. The work of L.G. laboratory is/has been supported by one National Institutes of Healt (NIH) R01 grant (#CA271915), by two Breakthrough Level 2 grants from the United States Deprtment of Defense (DoD) Breast Cancer Research Program (BCRP) (#BC180476P1, #BC210945), by a grant from the STARR Cancer Consortium (#I16-0064), by a Transformative Breast Cancer Consortium Grant from the United States DoD BCRP (#W81XWH2120034, PI: Formenti), by a U54 grant from NIH/NCI (#CA274291, PI: Deasy, Formenti, Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukaemia and Lymphoma Society (LLS), by a Rapid Response Grant from the Functional Genomics Initiative (New York, USA), by a pre-SPORE grant (PI: Demaria, Formenti), a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center (New York, USA), by startup funds from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA), and by startup funds from Fox Chase Cancer Center (Philadelphia, USA). The work of L.Z. is supported by the SEERAVE Foundation, European Union Horizon 2020 (Project Number: 825410 and Project Acronym: ONCOBIOME), INCa, ANR Ileobiome – 19-CE15-0029-01, ANR RHU5 “ANR-21-RHUS-0017” IMMUNOLIFE”, MAdCAM INCA_ 16698, Ligue contre le cancer, la Direction generale de l’offre de soins (DGOS), Prevalung (grant agreement number 101095604, Project Acronym: PREVALUNG EU, project title: Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception). The funders had no role in data collection and analysis, decision to publish, or the preparation of the manuscript.
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J.C. researched data for this manuscript. J.C., E.D., L.G. and L.Z. made a substantial contribution to discussions of content. J.C., G.K., L.G. and L.Z. wrote the manuscript, and all authors reviewed and/or edited the manuscript prior to submission.
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E.D. has acted as a consultant and/or adviser of Boehringer-Ingelheim and Merck Serono, has received research funding from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, IMCORE/Roche Genentech, Merck Serono and MSD, and is a founder of Graegis Pharmaceuticals. G.K. is an adviser of Hevolution and Institut Servier, is a scientific co-founder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio, is on the Board of Directors of the Bristol Myers Squibb Foundation France, is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders, and has received research funding from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage; his brother (Romano Kroemer) was an employee of Sanofi and now consults for Boehringer-Ingelheim. L.G. has acted as a consultant for and/or adviser of AstraZeneca, AbbVie, Boehringer-Ingelheim, EduCom, Inzen, Imvax, the Longevity Labs, the Luke Heller TECPR2 Foundation, Noxopharm, OmniSEQ, Onxeo, Promontory and Sotio, receives research funding from Lytix Biopharma, Promontory and Onxeo, and holds stock options in Promontory. L.Z. is a founder and president of the advisory board of everImmune and receives research funding from 9 meters, Daichi Sankyo, Kaleido and Pileje. J.C. declares no competing interests.
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Chen, J., Deutsch, E., Kroemer, G. et al. The microbiota in radiotherapy-induced cancer immunosurveillance. Nat Rev Clin Oncol 22, 667–679 (2025). https://doi.org/10.1038/s41571-025-01052-8
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DOI: https://doi.org/10.1038/s41571-025-01052-8
