Adenosine A_2A receptor as a potential target for improving cancer immunotherapy

The adenosine nucleoside performs a wide range of actions on various human tissues by activating four cell surface receptors. Adenosine A_2A receptors (A_2ARs) are widely expressed in the striatum, olfactory bulb, platelets, leukocytes, spleen, and thymus. They promote vasodilatation, platelet antiaggregatory effect, protection from ischemic damage, and regulation of sensorimotor neurons in basal ganglia. Adenosine signaling plays a vital part in modulating in vivo pathophysiological responses. A_2ARs are potent negative regulators of the antitumor and proinflammatory actions of activated T cells. This axis offers several therapeutic targets, the most important of which are A_2ARs, HIF-1α, and CD39/CD73. Downregulation of this axis increases the effectiveness of modern immunotherapeutic approaches against cancer, such as αCTLA-4/αPD-1. These discoveries have led to a promising novel role of antagonists of A_2AR in blocking angiogenesis in immunotherapy of cancer. A small molecule, AZD4635, strongly inhibits A_2AR, lowering cancer volume and increasing anticancer immunity. Deletion of A_2AR with CRISPR/Cas9 in both human and murine CAR T cells produces a substantial increase in the efficiency of these cells. This review asserts that inhibition of the adenosinergic pathway can boost antitumor immunity, and this axis should be a target for future immunotherapeutic strategies.