Mismatch Repair–Proficient Colorectal Cancer Can Evade Immune Surveillance through an Intrinsic Suppressive Program

Abstract Although microsatellite-instable (MSI) colorectal cancers, reflecting mismatch repair (MMR) deficiency, often respond to immune checkpoint inhibitors, microsatellite-stable (MSS) tumors remain largely resistant. This disparity is typically attributed to differences in neoantigen load. However, whether antigen-independent mechanisms contribute to immune evasion in MSS colorectal cancer remains unclear. To address this, we engineered a model in which MSI and MSS colorectal cancer cells express identical levels of a defined antigen recognized by T-cell receptor–engineered T cells. Despite equivalent antigen presentation, MSS tumors exhibited impaired T-cell activation, reduced cytotoxicity, and resistance to killing. We linked this immune evasion to the MSS tumor secretome, which suppressed immune responses even in immunogenic MSI cells by impairing immune synapse formation. Surfaceome profiling by mass spectrometry identified glycosylation-dependent alterations that impair immune recognition. Our findings demonstrate that MSS colorectal cancer evades immune attack via intrinsic secretome-driven mechanisms, independent of antigenicity. Targeting glycosylation-linked suppressive pathways may restore T-cell responsiveness and improve immunotherapy efficacy in MSS colorectal cancer. Significance: This study reveals that MMR-proficient colorectal cancers resist T-cell attack not only due to low neoantigen load but also through glycosylation-dependent, secretome-mediated immunosuppression. These findings uncover a previously unrecognized immune evasion mechanism and identify actionable pathways to restore immunotherapy responsiveness in resistant colorectal tumors.