Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation

Radiotherapy 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.