Ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and 5'-nucleotidase (CD73) axis (CD39/CD73 axis)

The extracellular ATP/adenosine axis, primarily driven by the ectonucleotidases CD39 (Ectonucleoside triphosphate diphosphohydrolase 1) and CD73 (5'-nucleotidase), serves as a fundamental metabolic switch that regulates immune responses [PMID: 31019211]. Regulatory T cells (Tregs) utilize this pathway to hydrolyze pro-inflammatory extracellular adenosine triphosphate (ATP), released during cell stress or death, into adenosine monophosphate (AMP) via CD39, and subsequently into adenosine via CD73 [PMID: 17906631]. In the tumor microenvironment, the resulting accumulation of adenosine acts as a potent immunosuppressant by binding to A2A and A2B receptors on effector immune cells, thereby facilitating tumor escape [PMID: 28429520]. Therapeutic strategies targeting this axis aim to block the enzymatic activity of CD39 or CD73 using monoclonal antibodies or small molecule inhibitors to restore an immunostimulatory environment [PMID: 32194705]. These agents, such as oleclumab and quemliclustat, are currently being investigated in clinical trials, often in combination with other immunotherapies like PD-1 inhibitors, to enhance anti-tumor efficacy in various solid malignancies [ClinicalTrials.gov]. Beyond oncology, this axis is also a focus in inflammatory and autoimmune diseases where modulating purinergic signaling can restore immune homeostasis [PMID: 23695310].

Other names

NTPDase1/5'-NT axisPurinergic signaling axisATP-adenosine pathwayCD39-CD73-adenosine pathwayExtracellular ATP-adenosine metabolic checkpoint

Inhibition of ectonucleotidase activity to prevent the conversion of pro-inflammatory ATP into immunosuppressive adenosine, thereby enhancing anti-tumor immunity.