Emerging roles of O-GlcNAcylation in tumorigenesis, immunosuppression and drug resistance (Review).

O-GlcNAcylation is a dynamic post-translational modification that is highly sensitive to cellular nutrient availability. Its cycling is tightly regulated by two enzymes with opposing activities: O-GlcNAc transferase (OGT), which catalyzes the addition of N-acetylglucosamine to serine and threonine residues of target proteins, and O-GlcNAcase (OGA), which removes this modification. Accumulating evidence indicates that elevated OGT expression and increased global O-GlcNAcylation are common features of multiple cancer types and are closely associated with tumor initiation, progression and a poor clinical prognosis. Aberrant O-GlcNAcylation plays a critical role in regulating a range of oncogenic processes, including metabolic reprogramming, cell proliferation, metastasis, epigenetic remodeling, immunosuppression and therapeutic resistance. By modifying key signaling molecules, transcription factors and metabolic enzymes, dysregulated O-GlcNAcylation rewires cellular signaling networks to promote malignant transformation and tumor adaptability. In the present review, the recent advances in molecular mechanisms of O-GlcNAcylation in tumorigenesis and cancer progression are systematically summarized. The emerging evidence supporting the therapeutic potential of targeting O-GlcNAcylation and highlight current challenges and future perspectives associated with the development of OGT- and OGA-based anticancer strategies are further discussed. Collectively, a deeper understanding of O-GlcNAcylation-mediated regulatory networks may facilitate the development of novel targeted therapies for cancer treatment.