Work

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

Year: 2025

Type: article

Abstract: 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.

Source: Cancer Letters

DOI: 10.1016/j.canlet.2025.218132