Aberrant Glycosylation in Cancer: From Immune Checkpoint Mechanisms to Glycan-Targeted Therapeutics

Aberrant glycosylation is a recurrent feature of cancer that can alter receptor signaling, cell adhesion, immune recognition, and therapeutic response. These effects arise from coordinated changes in nucleotide-sugar metabolism, glycosyltransferases and glycosidases, ER/Golgi processing, intracellular O-GlcNAc cycling, and glycosphingolipid biosynthesis. Rather than treating these alterations as isolated glycan classes, this review follows a mechanistic sequence from biosynthetic remodeling to tumor–immune regulation and clinical translation. We first summarize the biosynthetic basis of cancer-associated glycan remodeling and then examine its consequences at the tumor–immune interface, including glycosylation of PD-1/PD-L1, Siglec–sialoglycan signaling, galectin–glycan interactions, and other glycan-dependent immune regulators. Cell-intrinsic effects on growth, invasion, and metastasis are discussed as complementary background, while therapy resistance and microenvironmental remodeling are considered in relation to immune and translational phenotypes. We next assess glycoproteomic workflows for site-specific characterization, emphasizing pre-analytical control, enrichment bias, mass-spectrometric acquisition, and computational validation. Clinically, established glycoform assays and selected glycan-directed or glycoengineered therapeutics demonstrate that glycobiology can inform patient care, although the maturity of individual strategies remains uneven. Broader implementation will require improved tumor specificity, standardized analytical workflows, reproducible biomarker validation, and evidence-based patient stratification. By integrating biosynthesis, immune regulation, measurement, and therapy, this review distinguishes clinically established applications from mechanisms and strategies that still require prospective validation.