O‐GlcNAcylation Facilitates the Initiation and Progression of Digestive Tumors

The escalating global burden of digestive system cancers, marked by high morbidity, mortality, and drug resistance, necessitates a more profound understanding of the mechanisms underlying tumorigenesis. Accumulating evidence underscores the pivotal role of O‐GlcNAcylation—a dynamic posttranslational modification‐mediated by O‐GlcNAc transferase (OGT)—in promoting digestive system tumors. Elevated levels of O‐GlcNAcylation are intricately associated with tumor progression, metastasis, immune evasion, and chemotherapy resistance. Targeting OGT or its downstream effectors represents a promising strategy to overcome drug resistance and enhance therapeutic efficacy. This review innovatively integrates the core perspective of the metabolism–immune–epigenetics regulatory axis. Based on comprehensive preclinical and clinical evidence, it systematically elaborates on the translational potential of modulating O‐GlcNAcylation in precision oncology for digestive system tumors, while emphasizing the necessity for future in‐depth mechanistic studies and clinical validation.