Mechanisms Underlying Immunotherapy Resistance in Microsatellite-Stable Colorectal Cancer

Microsatellite-stable (MSS) colorectal cancer, representing approximately 80–85% of all cases, remains largely refractory to immune checkpoint inhibitors (ICIs) compared with microsatellite instability-high (MSI-H) tumors. This review synthesizes current evidence on the multifaceted mechanisms underlying ICI resistance in MSS colorectal cancer, encompassing tumor-intrinsic factors (low neoantigen burden, impaired antigen presentation, Wnt/β-catenin and MAPK pathway activation), an immunosuppressive tumor microenvironment (featuring regulatory T cells, myeloid-derived suppressor cells, M2-like macrophages, and cancer-associated fibroblasts), metabolic reprogramming, and gut microbiome dysbiosis. We further evaluate the interplay of environmental and lifestyle factors with these mechanisms and introduce the integrative framework of molecular pathological epidemiology. Translational strategies to overcome this resistance are discussed, including rational combinations with anti-angiogenic agents, radiotherapy, myeloid-targeting therapies, metabolic inhibitors, and microbiome modulation. Advancing the field will require biomarker-driven, adaptive clinical trials with embedded translational endpoints to enable personalized patient selection, optimize therapeutic efficacy, and manage toxicity.