PRMT5 Inhibitor Synergizes with Chemotherapy to Induce Resembling Mismatch Repair Deficiency and Enhance Anti‐TIGIT Therapy in Microsatellite‐Stable Colorectal Cancer

Microsatellite stable (MSS) colorectal cancer (CRC) is considered an "immune-cold" tumor, accounting for ≈85% of all CRC cases. The overall response rate to chemotherapy combined with immune checkpoint inhibitors in MSS CRC is typically less than 10%. The specific mechanism that enhances chemotherapy sensitivity and mediated immunogenicity renders MSS CRC more responsive to immunotherapy remains elusive. Experiments in this study identify a DNA damage repair-related epigenetic gene, protein arginine methyltransferase 5 (PRMT5), whose inhibition enhances Irinotecan (CPT-11) sensitivity and synergistically induces a postmeiotic segregation increased 2 (PMS2)-deficient-like state, leading to the release of cytosolic double-stranded DNA. This activates the cyclic GMP-AMP synthase (cGAS)-stimulator of the IFN gene (STING) signaling pathway, thereby enhancing anti-tumor immunotherapy through dendritic cell-T cell-dependent functions. Importantly, combining the epigenetic anti-tumor drug GSK3326595 with CPT-11 significantly upregulates the immune receptor tyrosine-based inhibitory motif (TIGIT) level on CD8+ T cells and subsequently demonstrates impressive anti-tumor efficacy in vivo when additional anti-TIGIT is included. Collectively, this study reveals the crucial role of PRMT5 blockade combined with CPT-11 in inducing a mismatch repair deficiency-like state and provides a novel triple-drug combination therapy strategy as a potential treatment for patients with MSS CRC.