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

## TL;DR

This paper reviews how glycosylation affects cancer radiotherapy outcomes by influencing DNA repair, immunity, and metabolism, offering new insights into improving treatment effectiveness.

## Contribution

The paper systematically categorizes glycosylation layers and their distinct roles in radiotherapy response, highlighting novel therapeutic opportunities.

## Key findings

- O-GlcNAcylation promotes post-irradiation survival through DNA repair signaling.
- N-glycosylation indirectly affects DDR by modulating proteostasis and receptor signaling.
- Glycosylation influences immune checkpoint stability and immune cell recruitment after radiotherapy.

## Abstract

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.