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

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. 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). 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. Colorectal cancer is a major cause of cancer-related illness and death worldwide. Immunotherapy, which helps the body’s immune system recognize and attack cancer cells, has improved treatment outcomes for some patients. However, most colorectal cancers respond poorly to currently available immunotherapies. This resistance is partly related to the tumor microenvironment, which includes immune cells, supporting tissues and other components surrounding cancer cells. One emerging area of research involves glycosylation, a biological process in which sugar molecules are attached to proteins and other cellular structures. These sugar modifications can influence how cancer cells grow, interact with surrounding tissues and escape immune attack. This review examines three important glycosylation processes – O-glycosylation, sialylation and fucosylation – and their potential roles in colorectal cancer. We introduce the concept of a colorectal cancer “glycocode,” a proposed framework for understanding how these sugar-related processes may collectively influence tumor behavior and immune responses. This framework is intended to guide future research and has not yet been clinically validated. Understanding these processes could help researchers develop new biomarkers for identifying patients who may benefit from particular treatments. It may also support investigations into therapies that modify sugar-related interactions to improve immunotherapy effectiveness. However, these approaches remain experimental, and further laboratory investigations, reliable biomarker testing and clinical trials are needed before they can be used routinely in patient care.