B3GNT5 encodes a beta-1,3-N-acetylglucosaminyltransferase that catalyzes the synthesis of lacto- and neolacto-series glycosphingolipids, notably Lc3Cer and nLc5Cer. The enzyme plays a central role in embryonic development, as B3gnt5-null mice are embryonic lethal prior to implantation 1. B3GNT5 is essential for synthesis of HNK-1 and Lewis X carbohydrate structures on glycolipids. In cancer, B3GNT5 is frequently overexpressed and amplified across multiple tumor types, including basal-like breast cancer, glioblastoma multiforme, and thymoma, where elevated expression correlates with poor survival 234. In basal-like breast cancer, B3GNT5 overexpression is driven by copy number amplification and promoter hypomethylation, and sustains cancer stem cell properties through synthesis of SSEA-1-bearing glycolipids 2. In glioblastoma, high B3GNT5 expression in glioma stem cells predicts shortened overall survival and correlates with classical and mesenchymal subtypes 3. A pan-cancer analysis revealed B3GNT5 expression associates with T-cell infiltration and immune checkpoints; however, antibody-driven B3GNT5 inhibition diminished T-cell responses, suggesting a complex immunomodulatory role 5. Functionally, B3GNT5 depletion accumulates precursor glycosphingolipids and increases chemoresistance 6. B3GNT5 represents a potential therapeutic target in cancer, with glycosphingolipid synthesis inhibition showing reversibility of immunomodulatory effects 7.