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22 reviewsSUMMARYThe mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an openconundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefitsof 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 (R1 and %3 Gy) and on the metabolicand 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-L1blockade, 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 firstor second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimaldosimetry and indications for ILDR to maximize its therapeutic potential.