Ectonucleoside triphosphate diphosphohydrolase 1, 5'-nucleotidase, and Adenosine A2A receptor signaling pathway (CD39/CD73/A2AR pathway)

The CD39-CD73-Adenosine A2A receptor signaling pathway is a fundamental immune-regulatory axis that controls the transition from a pro-inflammatory to an immunosuppressive extracellular environment (Antonioli et al., 2013, Nature Reviews Cancer). The process begins with the enzyme CD39 (Ectonucleoside triphosphate diphosphohydrolase 1), which hydrolyzes extracellular ATP and ADP into AMP (UniProt P49189). Subsequently, CD73 (5'-nucleotidase) converts AMP into adenosine, a potent immunosuppressive nucleoside (UniProt P21589). Adenosine then binds to the A2A receptor (ADORA2A), a G protein-coupled receptor expressed on various immune cells, leading to increased intracellular cAMP levels that inhibit the activity of T cells and NK cells while promoting regulatory T cell function (UniProt P29274; Vijayan et al., 2017, Nature Reviews Cancer). In many cancers, this pathway is upregulated within the tumor microenvironment to facilitate immune evasion and promote tumor progression. Therapeutic interventions targeting this pathway include monoclonal antibodies and small molecules designed to inhibit CD39 or CD73 enzymatic activity or to antagonize the A2A receptor, thereby restoring the host's anti-tumor immune response (Allard et al., 2017, Immunological Reviews).

Other names

Adenosinergic signaling pathwayATP-adenosine axisCD39-CD73-A2AR axisExtracellular purinergic signaling pathway

The pathway is targeted by inhibiting the enzymatic conversion of pro-inflammatory extracellular ATP to immunosuppressive adenosine via CD39 and CD73 inhibitors, or by blocking adenosine-mediated immunosuppressive signaling through A2A receptor antagonists (Antonioli et al., 2013, Nature Reviews Cancer).