Tumor microenvironment modulation for immunotherapy in colorectal cancer: integrating glycosylation into precision immuno-oncology

INTRODUCTION: Immunotherapy has transformed the treatment of several malignancies but provides durable benefit in colorectal cancer (CRC) primarily for mismatch repair-deficient or microsatellite instability-high tumors. Most microsatellite-stable (MSS) CRCs remain resistant because of a profoundly immunosuppressive tumor microenvironment (TME), necessitating new therapeutic strategies. AREAS COVERED: This review examines mechanisms of immune resistance within the CRC TME and evaluates current therapeutic approaches, including stromal remodeling, vascular normalization, metabolic reprogramming and immune modulation. It then critically assesses aberrant glycosylation as a regulator of tumor-immune interactions. We discuss how O-glycosylation, sialylation and fucosylation are associated with epithelial differentiation, immune suppression and stromal remodeling, and propose the CRC glycocode as a hypothesis-generating framework linking glycosylation programs with tumor biology, therapeutic vulnerability and patient stratification. Emerging glycan-directed biomarkers and therapies are reviewed in the context of precision immuno-oncology. Literature was identified through PubMed, Scopus, Web of Science and Google Scholar (2006-2026). EXPERT OPINION: Glycosylation represents an emerging area of investigation in colorectal cancer immunotherapy. Experimental and translational evidence supports further evaluation of glycan-mediated immune regulation and its potential therapeutic targeting. Whether glycosylation-directed interventions can improve outcomes in MSS CRC remains uncertain and requires biomarker-informed prospective clinical trials.