Mechanisms and Applications of OGT-Mediated O-GlcNAc Glycosylation in Malignant Tumors

O-GlcNAcylation is a dynamic and reversible post-translational modification that modulates key cellular processes, including transcriptional regulation, signal transduction, and metabolic adaptation. This modification is catalyzed by a unique enzyme pair: O-GlcNAc transferase (OGT), which installs O-GlcNAc moieties on serine/threonine residues, and O-GlcNAcase (OGA), which removes them. Aberrant O-GlcNAcylation has been implicated in the initiation and progression of multiple cancers, promoting tumor growth, metastasis, metabolic reprogramming, immune evasion, and resistance to therapy. Mechanistically, O-GlcNAcylation alters the function, localization, and stability of oncogenic proteins such as MYC, NF-B, and HIF-1, and interfaces with other post-translational modifications including phosphorylation and acetylation. Elevated OGT expression is frequently observed in cancer tissues and correlates with poor clinical outcomes. Targeting O-GlcNAcylation pathways has shown therapeutic potential in preclinical models by impairing tumor cell survival and stemness. Despite growing interest, major challenges remain, including the lack of selective OGT inhibitors and incomplete characterization of the O-GlcNAc proteome. Advances in single-cell multi-omics, spatial metabolomics, and glycoproteomics may facilitate the construction of tumor-specific O-GlcNAc maps and enable precision targeting of glycosylation-dependent vulnerabilities.