Abstract
Adenosine-mediated activation of A(2A)R drives immunosuppressive signaling in high-adenosine tumor microenvironments (TMEs), impeding anticancer immunity. Targeting A(2A)R with negative allosteric modulators (NAMs) is a promising approach for cancer immunotherapy: unlike the orthosteric antagonists currently in use, which face competitive and off-target limitations, NAMs leverage a noncompetitive, saturable mechanism that enhances receptor selectivity. The development of a novel series of A(2A)R NAMs demonstrates potent activity within high-adenosine TMEs, underscoring a significant translational potential in oncology.