GalNAc-Transferases in Cancer

<b>Background/Objectives</b>: The polypeptide N-acetylgalactosaminyltransferase (GALNT) family initiates mucin-type <i>O</i>-glycosylation, a post-translational modification that plays a pivotal role in cellular signaling, adhesion, and immune evasion. Dysregulated GALNT expression has been increasingly implicated in carcinogenesis. <b>Methods</b>: We reviewed the literature on the expression, function, and clinical relevance of GALNT isoforms across various cancers, with a focus on their mechanistic roles, biomarker potential, and therapeutic implications. <b>Results</b>: Aberrant GALNT expression is observed in numerous malignancies, including breast, colorectal, gastric, lung, ovarian, and hepatocellular carcinomas. Isoforms such as GALNT1, -T2, -T3, and -T14 contribute to tumorigenesis by modulating the glycosylation of mucins such as Mucin-1 (MUC1), epithelial growth factor receptors (EGFR), and other signaling proteins. These alterations promote cancer cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and chemoresistance. Deranged GALNT expression is frequently associated with poor prognosis, and certain GALNT genotypes predict treatment response. However, functional redundancy among isoforms poses challenges for selective targeting. <b>Conclusions</b>: Despite their strong potential as modulators of cancer progression, GALNTs face substantial limitations in terms of substrate identification, mechanistic clarity, immune relevance, and therapeutic tractability. Overcoming these challenges requires advanced glycoproteomics, development of isoform-specific tools, and integrated studies across cancer and immunology to fully harness GALNT biology for clinical benefit.