RMI2 Depletion Recovers cGAS-STING Signaling to Enhance Immunotherapy in Colorectal Cancer

Microsatellite-stable (MSS) colorectal cancers (CRCs) are largely refractory to immune checkpoint inhibitors (ICIs) due to immunologically "cold" tumor microenvironments (TMEs) characterized by limited T-cell infiltration. While RecQ-mediated genome instability 2 (RMI2) is known for regulating DNA repair, its role in anti-tumor immunity remains unclear. Here, we demonstrate that RMI2 acts as an adaptive oncoprotein in CRC by suppressing innate immune activation through enhanced homologous recombination repair (HRR). Mechanistically, RMI2 stabilizes BRCA1-RAD51 complexes, accelerates DNA double-strand break repair, and limits cytosolic DNA release. Conversely, RMI2 deficiency impairs HRR, causing cytosolic DNA accumulation, cGAS-STING pathway activation, and type I interferon signaling that boosts anti-tumor immunity. Notably, RMI2 knockout in mice synergizes with PD-1 blockade and fluorouracil to induce robust tumor regression and prolonged survival. These findings uncover a previously unrecognized role for RMI2 in maintaining immune evasion through the coordinated regulation of DNA repair and cGAS-STING-dependent innate immune signaling, positioning RMI2 as a promising therapeutic target to convert MSS CRCs from "cold" to "hot" tumors and overcome ICI resistance.