ENTPD2 (ectonucleoside triphosphate diphosphohydrolase 2) is an ecto-nucleotidase located on chromosome 9 that catalyzes the hydrolysis of extracellular nucleotide triphosphates 1. As a member of the NTPDase family, ENTPD2 regulates purinergic signaling by modulating extracellular ATP and adenosine levels 2. Unlike the well-characterized CD39/NTPDase1, ENTPD2 is predominantly expressed in tumor cells rather than immune cells and is enriched in tumor-derived exosomes 3. Mechanistically, exosomal ENTPD2 suppresses CD8+ T cell function through dual pathways: reducing extracellular ATP (inhibiting P2X7R-mediated NFATc1 signaling) while promoting ATP-to-adenosine conversion (activating immunosuppressive A2AR signaling) 3. This creates an immunosuppressive tumor microenvironment. Clinically, ENTPD2 is associated with poor prognosis in colon cancer, correlating with advanced TNM stage and increased tumor invasion depth 3. Elevated serum exosomal ENTPD2 inversely correlates with tumor-infiltrating CD8+ T cell expression. ENTPD2 has also emerged as a feature gene for Alzheimer's disease in Mendelian randomization screening 4 and as a master regulator in prostate cancer heterogeneity 5, with associations to cardiorenal complications in type 2 diabetes 6. These findings position ENTPD2 as an important therapeutic target for immunotherapy and metabolic diseases.