Radiotherapy-elicited cGAMP transfer by LRRC8 VRAC promotes anticancer T cell response

Abstract In addition to conducting Cl −efflux in response cell swelling, LRRC8 VRACs have been implicated transporting cGAMP the bystander cells reinforcing IFN-I combat HSV-1 infection. However, a plausible role of VRAC-mediated transfer cancer immunity and autoimmunity has not explored. Here, we demonstrate that radiation-triggered regression implanted tumors largely depends on host expression Lrrc8a, especially T dendritic compartments. Inducibly ablating Lrrc8a through tamoxifen or cell-specific depletion CD4-Cre led diminished CD8 infiltration. Moreover, loss also impaired granzymes IFN-γ tumor-infiltrated cells. Mechanistically, our data implicate tumor-derived ATP work together trigger STING activation IRF3/IRF7-mediated IFN-β Remarkably, cell-derived feeds back empower cell’s cytolytic capacity induction subset ISGs. radiotherapy, observation VRAC regulates anticancer extends chemotherapy. Together, study supports emerging notion both radio- chemotherapies ability boost reveal crucial for transport this process. Supported by grants from National Natural Science Foundation China.