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Protein O-GlcNAcylation has evolved from a metabolic curiosity into a master post-translational modification that enables cancer cells to translate nutrient availability into coordinated programs of proliferation, therapy resistance, and immune evasion. In this review, we argue that hyper-O-GlcNAcylation is not merely a passive consequence of the Warburg effect but an actively maintained stress-adaptive state that drives malignancy through parallel substrate-selective circuits rather than a single unified axis. We synthesize recent advances in four interconnected dimensions. Metabolically, OGT integrates glucose, lipid, and nucleotide metabolism by modifying key rate-limiting enzymes and is regulated by lineage-specific mechanisms. O-GlcNAcylation modulates responses to chemotherapy and radiotherapy, reinforces DNA damage repair, and controls senescence. Immunologically, it promotes tumor immune evasion by stabilizing PD-L1, reprogramming macrophages, suppressing NK and T cell function, and modulating cGAS-STING signaling, thereby influencing checkpoint blockade efficacy. In the tumor microenvironment, O-GlcNAc signaling remodels the extracellular matrix, drives angiogenesis, and maintains cancer stemness and mechanoadaptation. Collectively, we propose that substrate-selective O-GlcNAc circuits, rather than global OGT activity, are the key drivers of context-dependent malignancy. This framework highlights opportunities for developing next-generation low-toxicity therapeutics, including substrate-selective inhibitors and PROTAC degraders, in rational combinations with chemotherapy, radiotherapy, and immunotherapy.