A2AR NAM 45(University of Modena and Reggio Emilia)

Adenosine-mediated activation of A_2AR drives immunosuppressive signaling in high-adenosine tumor microenvironments (TMEs), impeding anticancer immunity. Targeting A_2AR 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_2AR NAMs demonstrates potent activity within high-adenosine TMEs, underscoring a significant translational potential in oncology.