Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients

• DOI: 10.1016/j.ccell.2025.02.010
• Publication Date: 2025-03-10T14:42:39Z
• Authors: Jianzhou Chen; Antonin Levy; Ai-Ling Tian; Xuehan Huang; Guoxin Cai; Marine Fidelle; Conrad Rauber; Pierre Ly; Eugénie Pizzato; Lisa Sitterle; Gianmarco Piccinno; Peng Liu; Sylvère Durand; Misha Mao; Liwei Zhao; Valerio Iebba; Hannah Felchle; Anne-Laure Mallar...; Julius Clemens Fi...; Simon Thomas; Tim F. Greten; Jennifer C. Jones; Cecilia Monge; Sandra Demaria; Silvia Formenti; Lorenzo Belluomini; Valeria Dionisi; Christophe Massard; Pierre Blanchard; Charlotte Robert; Clément Quevrin; Eloise Lopes; Céline Clémenson; Michele Mondini; Lydia Meziani; Yizhou Zhan; Chengbing Zeng; Qingxin Cai; Daphne Morel; Roger Sun; Pierre-Antoine La...; Monica Mangoni; Vanessa Di Cataldo; Chiara Arilli; Maike Trommer; Simone Wegen; Sebastian Neppl; Rachel P. Riechel...; Marcos P. Camanda...; Elson Santos Neto; Pierre-Edouard Fo...; Nicola Segata; Peter Holicek; Lorenzo Galluzzi; Aitziber Buqué; Carolina Alves Co...; Lisa Derosa; Guido Kroemer; Chuangzhen Chen; Laurence Zitvogel; Eric Deutsch

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