TPST2 (tyrosylprotein sulfotransferase 2) catalyzes the O-sulfation of tyrosine residues in polypeptides using 3'-phosphoadenylyl sulfate (PAPS) as a cosubstrate, functioning primarily in the Golgi apparatus 1. The enzyme requires SLC35B2 transporter to deliver PAPS into the Golgi where protein sulfation occurs 1. TPST2 modifies key cellular proteins including integrin β4, which when sulfated affects cell migration and metastasis 1, and IFNγ receptor 1 at tyrosine 397, thereby suppressing interferon-γ signaling and antigen presentation 2. Disease relevance is significant across multiple conditions. In pancreatic ductal adenocarcinoma, high TPST2 expression correlates with poor patient survival and promotes tumor growth and metastasis 1. In cancer immunotherapy, TPST2 acts as a tumor immunity suppressor, and its inhibition enhances anti-PD1 treatment efficacy by boosting tumor-infiltrating lymphocytes 2. Genetic variations in TPST2 influence HIV-1 disease progression, with certain SNPs associated with delayed progression and reduced CD4 T-cell activation 3. TPST2 also affects thyroid function, as mutations cause congenital hypothyroidism in mice, though this phenotype is genetically background-dependent 4. Clinically, TPST2 represents a promising therapeutic target, with small molecule inhibitors showing anti-tumor activity and synergistic effects with immunotherapy 5.