Immunotherapy Resistance in dMMR/MSI-H Colorectal Cancer: Unraveling Mechanisms and Exploring Overcoming Strategies.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Approximately 15% of localized and 5% of metastatic cases exhibit mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). While immune checkpoint inhibitors (ICIs) have revolutionized the first-line treatment for this subgroup, 15%-46% of patients experience primary resistance, and a subset of responders eventually acquires resistance. This review synthesizes the multifaceted mechanisms underlying ICI resistance in dMMR/MSI-H CRC. We delineate tumor-intrinsic alterations, including defects in the antigen presentation machinery (specifically transporter associated with antigen processing [TAP]1/TAP2 and β2-microglobulin [β2m]), oncogenic signaling via the Wnt/β-catenin and JAK/STAT pathways, and epigenetic remodeling involving ARID1A. Furthermore, we explore the role of the immunosuppressive tumor microenvironment (TME), characterized by T-cell exclusion and myeloid-derived suppressor cell (MDSC) accumulation. To address these barriers, we evaluate the clinical potential of third-generation ICIs targeting lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and TIGIT, as well as emerging biomarker strategies such as gut microbiome modulation and circulating tumor DNA (ctDNA) dynamics. By integrating these mechanistic insights with novel therapeutic approaches, including bispecific antibodies (BsAbs) and adoptive cell transfer, this review aims to provide a roadmap for overcoming resistance and advancing precision immunotherapy in dMMR/MSI-H CRC.