Adenosine A2A receptor (ADORA2A) (ADORA2A)

The Adenosine A2A receptor (ADORA2A) is a high-affinity G protein-coupled receptor that plays a pivotal role in regulating immune cell function within the tumor microenvironment (Sitkovsky et al., 2014, Cancer Immunol Res). When extracellular adenosine levels rise—often due to the enzymatic activity of CD39 and CD73—adenosine binds to ADORA2A on effector T cells, triggering the activation of adenylyl cyclase and increasing intracellular cyclic AMP (cAMP) levels (Ohta et al., 2006, Nature). This elevation of cAMP activates protein kinase A (PKA), which subsequently inhibits T cell receptor (TCR) signaling, leading to reduced T cell proliferation and impaired production of effector cytokines like IFN-gamma (Leone et al., 2018, Comput Struct Biotechnol J). Additionally, regulatory T cells (Tregs) can suppress effector T cells by directly transferring cAMP through gap junctions, further amplifying this inhibitory signaling axis (Bopp et al., 2007, J Exp Med). In oncology, ADORA2A is a major therapeutic target; small molecule antagonists are designed to block these suppressive signals and restore the anti-tumor activity of effector T cells, particularly when used in combination with PD-1/PD-L1 inhibitors (Vignali et al., 2023, Front Immunol). Beyond its role in the immune system, ADORA2A is also targeted in the central nervous system for the treatment of Parkinson's disease, where its antagonism modulates dopaminergic neurotransmission (Mizuno et al., 2013, Mov Disord).

Other names

A2ARADORA2AAdenosine receptor A2aADORA2

Antagonism of the Adenosine A2A receptor to prevent cAMP-mediated suppression of effector T cells and enhance anti-tumor immunity.