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

Chen, J.; Levy, A.; Tian, A. -L.; Huang, X.; Cai, G.; Fidelle, M.; Rauber, C.; Ly, P.; Pizzato, E.; Sitterle, L.; Piccinno, G.; Liu, P.; Durand, S.; Mao, M.; Zhao, L.; Iebba, V.; Felchle, H.; Mallard De La Varende, A. -L.; Fischer, J. C.; Thomas, S.; Greten, T. F.; Jones, J. C.; Monge, C.; Demaria, S.; Formenti, S.; Belluomini, L.; Dionisi, V.; Massard, C.; Blanchard, P.; Robert, C.; Quevrin, C.; Lopes, E.; Clemenson, C.; Mondini, M.; Meziani, L.; Zhan, Y.; Zeng, C.; Cai, Q.; Morel, D.; Sun, R.; Laurent, P. -A.; Mangoni, M.; Di Cataldo, V.; Arilli, C.; Trommer, M.; Wegen, S.; Neppl, S.; Riechelmann, R. P.; Camandaroba, M. P.; Neto, E. S.; Fournier, P. -E.; Segata, N.; Holicek, P.; Galluzzi, L.; Buque, A.; Alves Costa Silva, C.; Derosa, L.; Kroemer, G.; Chen, C.; Zitvogel, L.; Deutsch, E.

doi:10.1016/j.ccell.2025.02.010

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.