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.