O-glycosylation in Cancer: Emerging Paradigms and Prospects for Precision Oncology.

O-glycosylation is a key post-translational modification that profoundly shapes tumor biology by regulating cell proliferation, metastasis, and immune evasion. Aberrant O-glycosylation features truncated glycans such as Tn and sialyl-Tn antigens together with dysregulated glycosyltransferases and promotes oncogenesis in diverse malignancies. This review summarizes recent progress in elucidating the role of O-glycosylation in cancer with emphasis on its effects on cell-surface glycoproteins, intracellular signaling pathways, and emerging RNA modifications. Integration of multi-omics data and machine learning has transformed tumor classification and prognosis prediction through distinct glycosylation signatures and now supports personalized treatment strategies. Newly discovered O-glycosylation of RNA reveals additional regulatory layers and broadens the field of glycosylation research. Targeted interventions including glycosyltransferase inhibitors, gene editing, and combination with immunotherapy demonstrate promising therapeutic potential. Advanced high-throughput tools especially mass spectrometry and enzymatic release methods accelerate biomarker discovery and target validation. Collectively, this review underscores the multifaceted impact of O-glycosylation on cancer progression and treatment response while highlighting the urgent need for continued interdisciplinary collaboration to translate these findings into precision oncology and better patient outcomes.