ST8SIA6 (ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 6) encodes an alpha-2,8-sialyltransferase that catalyzes the formation of disialic acid linkages on glycoproteins and glycolipids, with preference for O-glycans over N-glycans or glycolipids as acceptor substrates. The enzyme generates α2,8-linked disialic acids that can bind to immune regulatory receptors including murine Siglec-E and human Siglec-7 and -9 1. ST8SIA6 expression is upregulated in many human tumors and associated with decreased survival in several cancers, including colon cancer 1. Functionally, ST8SIA6-expressing tumors exhibit faster growth and decreased survival by inhibiting antitumor immune responses through Siglec-E-dependent mechanisms 1. The enzyme alters macrophage polarization toward the immunosuppressive M2 phenotype, including upregulation of arginase 1. Conversely, ST8SIA6 downregulation is associated with enhanced cancer stemness and drug resistance in colorectal cancer following long-term plasticizer exposure 2. The ST8SIA6 antisense RNA (ST8SIA6-AS1) acts as an oncogenic long non-coding RNA in hepatocellular carcinoma and lung adenocarcinoma by functioning as a competing endogenous RNA that sponges various microRNAs 345.