B3GNT3 is a Golgi-localized glycosyltransferase that catalyzes beta-1,3-N-acetylglucosamine addition to form poly-N-acetyllactosamine and extended core 1 O-glycans 12. The enzyme modifies protein glycosylation patterns, which critically regulates immune checkpoint signaling and metabolic processes in cancer cells. Mechanistically, B3GNT3 glycosylates PD-L1, promoting PD-L1/PD-1 immune evasion in triple-negative breast cancer, while B3GNT3 downregulation enhances cytotoxic T cell-mediated anti-tumor immunity 3. In pancreatic cancer, B3GNT3 catalyzes N-glycosylation of 4F2hc (system Xc- subunit), stabilizing the protein and enhancing cystine uptake, thereby promoting ferroptosis resistance 4. B3GNT3 also suppresses migration and invasion in neuroblastoma by reducing T antigen formation and dampening FAK/Src/Akt signaling 5. B3GNT3 is significantly upregulated across multiple cancers including lung adenocarcinoma, pancreatic ductal adenocarcinoma, esophageal cancer, and colorectal cancer, correlating with poor prognosis, higher tumor grades, and reduced CD8+ T cell infiltration 6789. Rare variants in B3GNT3 show potential association with Parkinson's disease susceptibility, possibly through neuroinflammatory mechanisms 10. B3GNT3 represents a promising therapeutic target for multiple cancer types and immunotherapy enhancement.