ENPP3 is an extracellular ectonucleotide pyrophosphatase/phosphodiesterase that catalyzes the hydrolysis of nucleotide triphosphates (ATP, GTP, UTP, CTP) and plays a critical role in innate immune regulation 1. A major function involves hydrolyzing the immunostimulatory second messenger 2',3'-cGAMP into GMP, AMP, and inorganic phosphate, thereby suppressing STING-dependent type I interferon production 1. ENPP3 is hypoxia-inducible in clear-cell renal cell carcinoma (ccRCC) via HIF-1α and is significantly upregulated in RCC tissues, where it dampens anti-tumor immunity and predicts poor prognosis 2. In ccRCC, ENPP3 inhibition elevates extracellular cGAMP, expanding M1 macrophages and cytotoxic T cells while reducing regulatory T cells in a STING- and interferon-dependent manner 2. Beyond immune regulation, ENPP3 exhibits broader catalytic activity, hydrolyzing nucleotide sugars like UDP-GlcNAc and potentially modulating glycosylation 3. In endometriosis, promoter hypomethylation increases ENPP3 expression, activating the AKT/mTOR pathway and promoting ectopic endometrial cell invasion and migration 4. These findings position ENPP3 as a therapeutic target for cancer immunotherapy and a biomarker for endometrial receptivity and disease pathogenesis.