Adenosine A2A receptor (ADORA2A) and Adenosine A2B receptor (ADORA2B) (ADORA2A/ADORA2B)

The extracellular ATP-adenosine axis is a critical metabolic signaling pathway that regulates immune responses within the tumor microenvironment (TME). In conditions of cellular stress or hypoxia, such as in cancer, extracellular ATP is released and rapidly converted into adenosine by the ectoenzymes CD39 and CD73 (Antonioli et al., 2013). Adenosine then acts as a potent immunosuppressive signal by binding to the Adenosine A2A and A2B receptors (A2AR and A2BR) expressed on various immune cells, including T cells, NK cells, and myeloid cells (Sitkovsky et al., 2004). Activation of these G protein-coupled receptors increases intracellular cAMP, leading to the inhibition of effector cell function and the promotion of regulatory T cell activity. Consequently, the A2AR/A2BR axis has become a major focus in immuno-oncology, with several small-molecule antagonists in clinical development aimed at restoring anti-tumor immunity (Vijayan et al., 2017). Beyond cancer, these receptors play significant roles in inflammation, cardiovascular regulation, and neurodegenerative disorders like Parkinson's disease (UniProt P29274).

Other names

A2ARA2BRAdenosine A2 receptorP1 receptorsCD39/CD73/Adenosine axis

Antagonism of the A2A and A2B receptors to prevent adenosine-induced accumulation of intracellular cAMP in immune cells, thereby reversing immunosuppression and enhancing anti-tumor T-cell activity (Vijayan et al., 2017; Leone et al., 2018).