Low-dose metronomic chemotherapy triggers oxidized mtDNA sensing inside tumor cells to potentiate CD8+T anti-tumor immunity

Abstract

Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is emerging as a promising form of chemotherapy utilization. LDM chemotherapy exerts immunomodulatory effects. However, the underlying mechanism is not fully understood. Here we found that suppressing tumor growth by LDM chemotherapy was dependent on the activation of CD8⁺T cells. LDM chemotherapy potentiated the cytotoxic function of CD8⁺T cells by stimulating cancer-cell autonomous type I interferon (IFN) induction. Mechanistically, LDM chemotherapy evoked mitochondrial dysfunction and increased reactive oxygen species (ROS) production. ROS triggered the oxidation of cytosolic mtDNA, which was sensed by cGAS-STING, consequently inducing type I IFN production in the cancer cells. Moreover, the cGAS-STING-IFN axis increased PD-L1 expression and predicted favorable clinical responses to chemoimmunotherapy. Antioxidant N-acetylcysteine inhibited oxidized mtDNA-induced type I IFN production and attenuated the efficacy of combination therapy with LDM chemotherapy and PD-L1 blockade. This study elucidates the critical role of intratumoral oxidized mtDNA sensing in LDM chemotherapy-mediated activation of CD8⁺T cell immune response. These findings may provide new insights for designing combinatorial immunotherapy for cancer patients.

Keywords: Chemoimmunotherapy; Cytotoxic T lymphocytes; Low-dose metronomic chemotherapy; Oxidized mtDNA; Type I interferon; cGAS/STING.