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 deficiency impairs homologous recombination repair, 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. Our data reveal that RMI2 loss derepresses the cGAS-STING pathway by disrupting DNA repair homeostasis, thereby reversing immune evasion. This paradigm shift converts MSS CRCs into “hot” tumors and renders them responsive to ICI therapy, establishing RMI2 inhibition as a novel therapeutic avenue.