Glycosylation in colorectal cancer: From tumor-intrinsic signaling to the host-microbiome glyco-interface.

Aberrant glycosylation is increasingly recognized as a key regulatory layer in colorectal cancer (CRC), extending beyond tumor-cell-intrinsic signaling to shape the tumor microenvironment and host-microbiome interactions. In the immune compartment, glycosylation modulates the stability and activity of classical checkpoints, including PD-L1, while tumor-associated glycans engage MGL, DC-SIGN, Siglecs, and galectins to form glyco-immune checkpoints that influence T-cell dysfunction, macrophage polarization, dendritic-cell tolerance, and NK-cell activity. These mechanisms support emerging glyco-immunotherapeutic strategies such as targeted desialylation, glycoform-specific targeting, and combination with immune checkpoint blockade. Glycosylation also functions as a molecular language at the host-microbiome interface. Site-specific epithelial glycoproteins, mucin O-glycoforms, bidirectional host-bacterial fucosylation, IgA-associated glycan recognition, and microbial glycan utilization may collectively shape CRC-associated dysbiosis and mucosal inflammation. Integrating stool glycoproteomics with microbiome profiling may further enable noninvasive screening and patient stratification. This review highlights glycosylation as a multidimensional interface linking tumor biology, antitumor immunity, and microbiome ecology, with implications for biomarker development and precision therapy in CRC.