Modulation of N-glycosylation in the PD-1: PD-L1 axis as a strategy to enhance cancer immunotherapies

The modulation of the N-glycosylation status in immune checkpoints, particularly the PD-1/PD-L1 axis, has emerged as a promising approach to enhance cancer immunotherapies. While immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 have achieved significant clinical success, recent studies highlight the critical role of N-glycosylation in regulating their expression, stability, and function. Alterations in N-glycosylation might affect the efficacy of ICIs by modulating the interactions between immune checkpoints and antibodies used in therapy. This review focuses on the glycosylation of PD-1 and its ligands PD-L1 and PD-L2, examining how N-glycans influence immune responses and contribute to immune evasion by tumors. It explores innovative strategies to modulate glycosylation in tumor and immune cells, including the use of N-glycosylation inhibitors and novel genetic manipulation techniques. Understanding the interplay between N-glycosylation and immune checkpoint functions is essential for optimizing immunotherapy outcomes and overcoming therapeutic resistance in cancer patients.