Chemotherapy potentiates CD8+ T cell cytotoxicity through stimulating cancer cell-autonomous type I IFN induction via oxidized mtDNA sensing

Abstract In addition to the direct tumor cell cytotoxicity, chemotherapy also plays roles in modulating immune response. However, the underlying mechanism is not fully understood. Here we found that chemotherapy enhanced tumor cell antigen presentation to facilitate CD8+ T cell cytotoxic function. Cancer cell-autonomous type I IFN induction stimulated by chemotherapy was critical for CD8+ T cell cytotoxicity. Mechanistically, chemotherapy impaired mitochondrial function and anti-oxidant capacity, which increased reactive oxygen species (ROS) production. ROS triggered oxidized mtDNA accumulation in the cytosol of tumor cells and subsequently activated cGAS-STING signaling to drive type I IFN induction. cGAS-STING-IFN axis increased PD-L1 expression and predicted effective clinical responses to chemoimmunotherapy. Our findings highlight that a suitable dose of chemotherapy activates CD8+ T cell immunity instead of directly inducing intense tumor cell toxicity, which may alleviate the side effects of chemotherapy and potentiate the sensitivity to immune checkpoint inhibitors (ICIs). Screening chemotherapeutic drugs or developing new drugs which can stimulate type I IFN production in the tumor cells efficiently promote anti-tumor immunity and will be beneficial for chemoimmunotherapy. Conversely, antioxidants like N-acetylcysteine which impede type I IFN induction, attenuate the therapeutic efficacy and will be unfavorable for patients that are receiving chemoimmunotherapy.