ST6GALNAC6 is an α-2,6-sialyltransferase that catalyzes the transfer of sialyl groups from CMP-NeuAc onto glycoproteins and glycolipids, forming α-2,6-linkages 1. The enzyme preferentially acts on glycolipids, mediating ganglioside biosynthesis and generating disialyl structures including disialyl Lewisa, a cancer-associated antigen 2. ST6GALNAC6 also catalyzes formation of the atypical Neu5Acα2-6GlcNAc linkage found in human milk oligosaccharides 3. Functionally, ST6GALNAC6-mediated sialylation is critical for intestinal homeostasis. Mice lacking St6galnac6 exhibit reduced mucin sialylation, producing thinner, more permeable mucus with increased bacterial invasion and heightened susceptibility to intestinal inflammation 4. In colorectal cancer, ST6GALNAC6 expression is epigenetically silenced through NF-κB/EZH2/YY1 and BGN/TLR4/NF-κB axes, reducing immunosuppressive Siglec ligand glycans and promoting carcinogenesis 56. Conversely, stromal cells in colorectal cancer exhibit high ST6GALNAC6 expression, generating hypersialylated glycans that suppress innate immunity via Siglec-10 engagement on macrophages and NK cells 7. In gastric cancer, FOXO-mediated ST6GALNAC6 upregulation promotes elevated sialylation in cancer stem cells, supporting tumor growth 2. ST6GALNAC6 represents a therapeutic target for reversing immunosuppression in cancer while maintaining protective mucosal immunity.