Beyond immune suppression: Revisiting adenosine A2A receptor biology in CD8 + T-cell differentiation, metabolic fitness and cancer immunotherapy

Extracellular adenosine is a major immunosuppressive metabolite of the tumor microenvironment and a key barrier to anti-tumor immunity. Generated from ATP by the ectonucleotidases CD39 and CD73, it signals mainly through the high-affinity A2A adenosine receptor (A2AR). Although A2AR is regarded as an inhibitory immune checkpoint, recent work shows that its functions extend beyond immediate effector suppression to the regulation of metabolic fitness, mitochondrial homeostasis, and CD8+ T-cell differentiation. Notably, both sustained A2AR activation and complete receptor deficiency can drive terminal exhaustion through distinct mechanisms, and CD73 and extracellular adenosine are not biologically equivalent. Here we summarize adenosine signaling, the cell-specific roles of the A2AR axis, and the clinical development of A2AR-targeting immunotherapies. We identify the principal obstacles to therapeutic translation and advance biomarker-guided, calibrated modulation of A2AR signaling as a testable hypothesis rather than an established therapeutic principle, one that now requires comparative exposure–response and longitudinal intervention studies.