The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA 19111 2497 USA

Department of Clinical Oncology AC Camargo Cancer Center São Paulo 01509 900 Brazil

Department of Computational Cellular and Integrative Biology University of Trento 38123 Trento Italy

Department of Computational Cellular and Integrative Biology University of Trento 38123 Trento Italy; IEO Istituto Europeo di Oncologia IRCCS 20139 Milan Italy

Department of Radiation Oncology AC Camargo Cancer Center São Paulo 01509 001 Brazil

Department of Radiation Oncology Cancer Hospital of Shantou University Medical College Shantou 515031 China

Department of Radiation Oncology Cyberknife and Radiotherapy Faculty of Medicine and University Hospital Cologne 50937 Cologne Germany

Department of Radiation Oncology Cyberknife and Radiotherapy Faculty of Medicine and University Hospital Cologne 50937 Cologne Germany; Center for Integrated Oncology Faculty of Medicine and University Hospital Cologne University of Cologne 50937 Cologne Germany

Department of Radiation Oncology Cyberknife and Radiotherapy Faculty of Medicine and University Hospital Cologne 50937 Cologne Germany; Center for Integrated Oncology Faculty of Medicine and University Hospital Cologne University of Cologne 50937 Cologne Germany; Center for Molecular Medicine Cologne University of Cologne 50931 Cologne Germany; Olivia Newton John Cancer Wellness and Research Centre Austin Health Department of Radiation Oncology Heidelberg VIC 3084 Melbourne Australia

Department of Radiation Oncology Gustave Roussy Cancer Campus 94805 Villejuif France

Department of Radiation Oncology University of Verona Hospital Trust 37126 Verona Italy

Department of Radiation Oncology Weill Cornell Medicine New York NY 10065 USA

Department of Radiation Oncology Weill Cornell Medicine New York NY 10065 USA; Sotio Biotech 19000 Prague Czech Republic

Faculté de Médecine Université Paris Saclay 94270 Kremlin Bicêtre France; Department of Radiation Oncology Gustave Roussy Cancer Campus 94805 Villejuif France

Faculté de Médecine Université Paris Saclay 94270 Kremlin Bicêtre France; INSERM U1030 Radiothérapie Moléculaire et Innovations Thérapeutiques Gustave Roussy Cancer Campus 94805 Villejuif France

Faculté de Médecine Université Paris Saclay 94270 Kremlin Bicêtre France; INSERM U1030 Radiothérapie Moléculaire et Innovations Thérapeutiques Gustave Roussy Cancer Campus Gustave Roussy Cancer Campus 94805 Villejuif France

Gastrointestinal Malignancy Section Thoracic and Gastrointestinal Malignancies Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Gustave Roussy Cancer Campus 94805 Villejuif France

Gustave Roussy Cancer Campus Clinicobiome 94805 Villejuif Cedex France

Gustave Roussy Cancer Campus UMR 1015 Equipe Labellisée Ligue Nationale contre le Cancer 94805 Villejuif France

Gustave Roussy Cancer Campus UMR 1015 Equipe Labellisée Ligue Nationale contre le Cancer 94805 Villejuif France; Department of Gastroenterology and Infectious Diseases University Hospital Heidelberg 69120 Heidelberg Germany

Gustave Roussy Cancer Campus UMR 1015 Equipe Labellisée Ligue Nationale contre le Cancer 94805 Villejuif France; Department of Radiation Oncology Cancer Hospital of Shantou University Medical College Shantou 515031 China

IHU Méditerranée Infection 13005 Marseille France

INSERM U1030 Radiothérapie Moléculaire et Innovations Thérapeutiques Gustave Roussy Cancer Campus 94805 Villejuif France

Medical Physics Unit Azienda Ospedaliero Universitaria Careggi 50134 Florence Italy

Metabolomics and Cell Biology Platforms UMS AMMICa Gustave Roussy Cancer Campus 94805 Villejuif France

Metabolomics and Cell Biology Platforms UMS AMMICa Gustave Roussy Cancer Campus 94805 Villejuif France; Centre de Recherche des Cordeliers INSERM U1138 Équipe Labellisée Ligue Nationale contre le Cancer Université Paris Cité Sorbonne Université 75006 Paris France

Metabolomics and Cell Biology Platforms UMS AMMICa Gustave Roussy Cancer Campus 94805 Villejuif France; Centre de Recherche des Cordeliers INSERM U1138 Équipe Labellisée Ligue Nationale contre le Cancer Université Paris Cité Sorbonne Université 75006 Paris France; General Surgery Cancer Center Department of Breast Surgery Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou Zhejiang 310014 China; Zhejiang University Hangzhou Zhejiang 310000 China

Metabolomics and Cell Biology Platforms UMS AMMICa Gustave Roussy Cancer Campus 94805 Villejuif France; Centre de Recherche des Cordeliers INSERM U1138 Équipe Labellisée Ligue Nationale contre le Cancer Université Paris Cité Sorbonne Université 75006 Paris France; Institut du Cancer Paris CARPEM Department of Biology Hôpital Européen Georges Pompidou AP HP 75015 Paris France

Metabolomics and Cell Biology Platforms UMS AMMICa Gustave Roussy Cancer Campus 94805 Villejuif France; Centre de Recherche des Cordeliers INSERM U1138 Équipe Labellisée Ligue Nationale contre le Cancer Université Paris Cité Sorbonne Université 75006 Paris France; Technical University of Munich TUM School of Medicine and Health Klinikum rechts der Isar Department of Radiation Oncology 81675 Munich Germany

Radiation Oncology Unit Azienda Ospedaliero Universitaria Careggi 50134 Florence Italy

Radiotherapy Unit Department of Experimental and Clinical Biomedical Sciences Mario Serio University of Florence 50134 Florence Italy

Section of Innovation Biomedicine Oncology Area Department of Engineering for Innovation Medicine of Verona 37134 Verona Italy

Translational Nanobiology Section Laboratory of Pathology National Cancer Institute National Institutes of Health Bethesda MD 20892 USA; Radiation Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

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