Currently, the most
promising therapeutic modality for cancer treatment
is the blockade of immune checkpoint pathways, which has revolutionized
cancer therapy in the past 15 years. Strategies targeting and modulating
adenosine A2A receptor (A2AR), an emerging alternative
immune checkpoint, have shown the potential to produce significant
therapeutic effects. In this review, we describe the immunosuppressive
activities of A2AR and A2BR in the tumor microenvironment
(TME), followed by a summary and discussion of the structure–activity
relationship (SAR) of the A2AR (and dual A2AR/A2BR) antagonists that have been experimentally confirmed
to exert oncoimmunological effects. This review also provides an update
on the compounds under clinical evaluation and insights into the ligand
binding modes of the receptor.