CD73

CD73 (ecto-5'-nucleotidase, NT5E) is a 70-kDa glycosylphosphatidylinositol-anchored ectoenzyme that, together with CD39, executes the two-step enzymatic cascade converting extracellular pro-inflammatory ATP into adenosine: CD39 hydrolyzes ATP/ADP to AMP, and CD73 dephosphorylates AMP to adenosine. The adenosine generated binds A2A and A2B receptors on T cells, NK cells and myeloid cells, raising intracellular cAMP and potently suppressing cytotoxicity, proliferation, cytokine release and dendritic-cell maturation, while promoting Treg and myeloid-derived suppressor cell expansion. CD73 is constitutively low but strongly induced by hypoxia (HIF-1α), TGF-β and PD-1 signaling within tumors, making it a hypoxia-adaptive immune checkpoint. CD73 overexpression predicts poor outcome and anti-PD-1 resistance in melanoma, ovarian, breast and lung cancers; anti-CD73 antibodies (oleclumab, mupadolimab) and A2A receptor antagonists are in clinical development as immunotherapy combinations. CD73 loss mutations cause painful calcification of lower-extremity arteries (arterial calcification due to CD73 deficiency, ACDC).