Adenosine A2a receptor (A2aR) and Adenosine A2b receptor (A2bR) (A2aR/A2bR)

The Adenosine A2a receptor (A2aR) and Adenosine A2b receptor (A2bR) are G protein-coupled receptors that function as critical metabolic checkpoints within the tumor microenvironment (UniProt: P29274, P29275). Under conditions of cellular stress or hypoxia, extracellular adenosine levels rise and activate these receptors to suppress the immune system; A2aR primarily inhibits the effector functions of T cells and natural killer cells, while A2bR promotes the activity of myeloid-derived suppressor cells and facilitates tumor angiogenesis (Walters et al., 2018). Etrumadenant (AB928) is a small-molecule dual antagonist designed to block both receptors simultaneously, providing a more robust reversal of adenosine-mediated immunosuppression than antagonists targeting only a single receptor. By inhibiting these pathways, etrumadenant aims to restore anti-tumor immunity and enhance the efficacy of other treatments, such as PD-1/PD-L1 inhibitors and chemotherapy. This dual-targeting strategy is currently being evaluated in clinical trials for various solid tumors, including colorectal, lung, and prostate cancers (Arcus Biosciences, 2024). The therapeutic objective is to overcome the immune-shielding effects of high adenosine levels, thereby improving patient outcomes in treatment-resistant malignancies.

Other names

ADORA2AADORA2BAdenosine A2a receptorAdenosine A2b receptorA2A adenosine receptorA2B adenosine receptorAdenosine receptor A2aAdenosine receptor A2b

Etrumadenant acts as a potent, competitive dual antagonist of the Adenosine A2a and A2b receptors, preventing adenosine-mediated increases in intracellular cAMP that suppress immune cell activation and promote tumor progression (Walters et al., 2018, Cancer Research).