Regulation of glycosylation in radiotherapy: exploring the multiple effects of DNA damage, immune response, stromal microenvironment and metabolism.

Radiotherapy remains a central component of cancer care, but its clinical benefit is frequently compromised by intrinsic or acquired radioresistance. Growing evidence indicates that glycosylation, one of the most prevalent post-translational modifications, is not merely a bystander but an active determinant of how tumors respond to irradiation. In this review, we organize the literature by separating glycosylation into mechanistically distinct layers-O-GlcNAcylation, N-glycosylation, mucin-type O-glycosylation, and terminal sialylation-and summarize how each layer shapes radiotherapy outcomes through effects on the DNA damage response (DDR), antitumor immunity, stromal remodeling, and metabolic adaptation. Within DDR, dynamic O-GlcNAc cycling governed by OGT and OGA can promote repair signaling and post-irradiation survival. By contrast, changes in N-glycan processing more often affect DDR indirectly, for example by tuning proteostasis and receptor-dependent signaling, and in certain settings through PD-L1 trafficking and functions. In the tumor immune microenvironment, glycosylation influences both checkpoint stability and glycan-lectin interactions (such as sialoglycan-Siglec pathways) that can dampen immunity after radiotherapy. Irradiation can also remodel glycosylation in endothelial cells and the extracellular matrix, with consequences for immune-cell recruitment and fibrotic responses. Finally, radiation-induced metabolic stress may shift nucleotide-sugar availability (including HBP-derived UDP-GlcNAc), linking metabolic state to glycosylation programs and radiosensitivity. We conclude by outlining therapeutic opportunities as well as practical hurdles-such as specificity, toxicity, and delivery-that must be addressed before glycosylation-targeted radiosensitization can be translated to the clinic.