Mechanisms of immune resistance in microsatellite-stable colorectal cancer

Microsatellite-stable (MSS) colorectal cancer (CRC) accounts for approximately 85% of all CRC cases and exhibits limited responsiveness to immune checkpoint inhibitors (ICIs), representing a major challenge in current cancer immunotherapy. At the tumor-cell intrinsic level, low tumor mutational burden (TMB), impaired neoantigen generation, aberrant activation of oncogenic pathways such as WNT/β-catenin signaling, and defects in interferon-γ signaling contribute to impaired immune recognition and immune escape. Within the TME, the accumulation of immunosuppressive populations, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), together with extracellular matrix remodeling and chemokine dysregulation, establishes an immune-excluded microenvironment that restricts effective antitumor immune responses. Furthermore, metabolic alterations, including enhanced glycolysis, lactate accumulation, and amino acid metabolic reprogramming, impair immune cell function and promote immunosuppression. Epigenetic modifications, including DNA methylation, histone remodeling, and non-coding RNA regulation, further contribute to the silencing of immune-related genes and reinforcement of immune evasion. In addition, recent advances in single-cell sequencing and spatial transcriptomics have provided unprecedented insights into the cellular heterogeneity and spatial organization of MSS CRC immune ecosystems. This review summarizes current knowledge regarding the molecular and cellular mechanisms driving immune resistance in MSS CRC and discusses future therapeutic opportunities for transforming immunologically "cold" MSS tumors into responsive immune microenvironments.