Deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (CRC) is highly sensitive to immune checkpoint inhibitors due to the high tumor mutation load and neoantigen enrichment. However, 45%-60% of patients exhibit primary or acquired immunotherapy resistance. The mechanisms underlying this resistance are complex, involving tumor microenvironment heterogeneity, co-expression of multiple immune checkpoints, aberrant activation of oncogenic pathways, metabolic dysregulation, intestinal microbiota imbalance, HLA-Ⅰ molecule defects, and epigenetic regulation. Current strategies aimed at reversing immunotherapy resistance include combination immunotherapies, personalized neoantigen vaccines, intestinal microbiota transplantation, epigenetic interventions, and adoptive immune cell therapies. Further analysis of the potential mechanisms of immune therapy resistance in dMMR/MSI-H metastatic CRC, and the exploration of current strategies to overcome resistance can provide a theoretical basis for reversing the immunotherapy resistance in such patients.