摘要：SummaryRadiotherapy combined with immune checkpoint blockade has gradually revealed the superiority in the antitumor therapy; however, the contribution of host PD-L1 remains elusive. In this study, we found that the activation of CD8+T cells was strikingly increased in both irradiated PD-L1-expressing primary tumor and distant non-irradiated syngeneic tumor in PD-L1-deficient mouse host, and thus enhanced radiation-induced antitumor abscopal effect (ATAE) by activating cGAS-STING pathway. Notably, the autophagy inhibitors distinctively promoted dsDNA aggregation in the cytoplasm and increased the release of cGAS-STING-regulated IFN-β from irradiated cells, which further activated bystander CD8+T cells to release IFN-γ and contributed to ATAE. These findings revealed a signaling cascade loop that the cytokines released from irradiated tumor recruit CD8+T cells that in turn act on the tumor cells with amplified immune responses in PD-L1-deficient host, indicating a potential sandwich therapy strategy of RT combined with PD-L1 blockage and autophagy inhibition.Graphical abstractDisplay OmittedHighlights•IR combined with PD-L1−/−promotes the proliferation and differentiation of CD8+T cells•IFN-β from IR-tumor stimulates IFN-γ from bystander CD8+T cells, more profound in PD-L1−/−mice•Autophagy inhibition boosts IR-induced dsDNA and cGAS-STING in the tumor of PD-L1−/−mice•Autophagy inhibition enhances IR-induced ATAE by activating cGAS-STING under PD-L1−/−statusMicroenvironment; Radiation biology; Immune response; Cancer
