Targeting DRP1 promotes radiotherapy-induced antitumor immunity via mitochondrial DNA-mediated cGAS-STING signaling in KRAS-mutated colorectal cancer

Oncogenic KRAS causes the immunosuppressive tumor microenvironment (TME) to decrease the therapeutic response to radiotherapy (RT) and is associated with poor outcomes. In this study, we observed that constitutive dynamin-related protein 1 (DRP1) phosphorylation by oncogenic KRAS resulted in a decrease in mitochondrial DNA (mtDNA) content, leading to attenuated radiotherapy-induced cGAS/STING-driven type I IFN secretion. Targeting DRP1 phosphorylation enhanced cytosolic mtDNA release to promote cGAS/STING activation in response to radiotherapy. Disruption of cGAS-STING signaling limited the immune-enhancing effect of DRP1 targeting on type I IFN production and T-cell killing ability. Targeting DRP1 increased the therapeutic response and induced systemic antitumor immunity, accompanied by increased type I IFN signaling and intratumoral infiltration of immune cells in response to radiotherapy. Notably, the immune-enhancing effects of DRP1 inhibition were impaired by IFN receptor blockade. Moreover, dual targeting of DRP1 and MEK significantly enhanced the therapeutic response to RT in a KRAS G12D -driven CRC model, providing its clinical relevance to target undruggable KRAS G12D -driven CRC patients. Taken together, these findings reveal that DRP1 phosphorylation-mediated mtDNA decrease is a suppressor of antitumor immunity, suggesting that targeting DRP1 could be used to increase tumor immunogenicity and improve responsiveness to radiotherapy, especially in oncogenic KRAS-driven CRC patients. • Oncogenic KRAS decreases mitochondrial dsDNA level via DRP1 phosphorylation. • Targeting DRP1 enhances Mito-dsDNA/STING signaling to increase immunogenicity. • Targeting DRP1 reshapes tumor microenvironment to enhance the efficacy of RT. • Dual targeting MEK and DRP1 increases the response to RT in KRAS-mutated cancers.