Tn-Associated Truncated O-linked N-acetylgalactosamine (O-GalNAc) Glycosylation in Pancreatic Cancer: Mechanisms, Biomarkers, and Therapeutic Translation

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies because of early metastatic spread, limited opportunities for early detection, and rapid development of treatment resistance. Among the molecular changes that accompany PDAC progression, aberrant mucin-type O-linked N-acetylgalactosamine (O-GalNAc) glycosylation has emerged as a recurrent feature of malignant pancreatic cells. When O-glycan maturation is disrupted, the normally transient Tn antigen (Tn, GalNAcα-O-Ser/Thr) can persist on cell-surface and secreted glycoproteins. Increasing evidence links this altered glycosylation state to tumor progression, but its biological meaning is more complex than Tn abundance alone. The effects of Tn-associated glycosylation depend on which protein carries the glycan, how that carrier is modified, and the cellular and microenvironmental setting in which it is expressed. Accordingly, broad O-glycan truncation can produce divergent biological effects across experimental models. In PDAC, these changes have been linked to altered receptor and adhesion signaling, invasive and stem-like phenotypes, metabolic and treatment adaptation, and interactions with immune and stromal cells. This carrier and glycoform heterogeneity also complicates the use of Tn as a biomarker or therapeutic target. This review therefore examines Tn-associated O-GalNAc remodeling from glycan biosynthesis to carrier-specific function and tumor-ecosystem effects, while distinguishing evidence from human PDAC, pancreatic cancer models, and other tumor types. We further evaluate the current diagnostic, prognostic, and therapeutic evidence and define the molecular resolution needed to move Tn-associated glycoforms toward clinically useful biomarkers and targeted therapies.