m ⁶ A RNA modification programs the immunosuppressive tumor microenvironment in colorectal cancer

Despite advances in immunotherapy, colorectal cancer (CRC) often progresses by fostering a profoundly immunosuppressive tumor microenvironment (TME). Emerging research underscores the pivotal role of post-transcriptional regulation in programming this immune-evasive niche. This review synthesizes accumulating evidence to propose a unifying paradigm wherein the epitranscriptomic modification N 6 -methyladenosine (m 6 A) acts as a master regulator orchestrating the immunosuppressive ecosystem in CRC. We detail how m 6 A operates through a multi-tiered network: by intrinsically reprogramming CRC cells to enhance immune checkpoint expression, secrete immunosuppressive factors, and activate pro-survival pathways; by dynamically governing intercellular communication through extracellular vesicles and non-coding RNAs; and by extrinsically reprogramming stromal and immune cells within the CRC TME toward pro-tumorigenic phenotypes. This coordinated regulation ensures precise execution of immune-evasive programs, yet its outcome is highly context-dependent – shaped by cell type, target selectivity, disease stage, and microenvironmental cues. The translational implications are substantial: m 6 A-related signatures offer novel biomarkers for prognosis and prediction of immunotherapy response, while targeting the m 6 A machinery shows synergistic potential with existing immunotherapies. Future efforts must focus on spatial epitranscriptomics, decoding context-dependent regulation, integrating the gut microbiota axis, and developing precise delivery systems. Deciphering the m 6 A-mediated immunoregulatory network thus provides not only a novel mechanistic framework for understanding CRC immune evasion but also a roadmap for translating these insights into biomarker-driven combination immunotherapy strategies, moving toward a new era of precision cancer immunology.