GALNT6 is a polypeptide N-acetylgalactosaminyltransferase that catalyzes the initial transfer of N-acetyl-D-galactosamine to serine or threonine residues on target proteins, initiating O-linked oligosaccharide biosynthesis. The enzyme modifies diverse substrates including mucins, fibronectin, and the phosphate-regulating hormone FGF23, and may participate in synthesis of oncofetal fibronectin. GALNT6 expression is frequently elevated in multiple cancer types and is associated with poor clinical outcomes. In lung adenocarcinoma, GALNT6 overexpression promotes epithelial-mesenchymal transition and metastasis by O-glycosylating the chaperone protein GRP78, which activates the MEK1/2/ERK1/2 signaling pathway 1. In breast cancer, GALNT6 drives tumorigenicity through the β-catenin/MUC1-C signaling axis and promotes stemness and drug resistance via association with GDF-15 2. Recent work reveals that GALNT6 also promotes immune evasion in pancreatic cancer by blocking STING signaling and stabilizing PD-L1 expression 3, while driving lenvatinib resistance in hepatocellular carcinoma through O-glycosylation-mediated modulation of autophagy and cancer-associated fibroblast activation 4. Targeting GALNT6 and O-glycosylation pathways shows promise as a therapeutic strategy, potentially enhancing the efficacy of immunotherapy and tyrosine kinase inhibitors across multiple malignancies.