Cancer progression is closely associated with metabolic reprogramming and immune evasion. Extracellular adenosine (eADO) metabolism regulates adenosine receptor activation within the tumor microenvironment (TME). Predominantly through the adenosine A2A receptor (A2AR), and in some contexts through the adenosine A2B receptor (A2B receptor), eADO signaling suppresses antitumor immune responses and contributes to resistance to immunotherapy. Production of eADO is largely driven by ecto-5'-nucleotidase (CD73), which catalyzes the conversion of eADO monophosphate (AMP) into eADO. In parallel, methylthioadenosine phosphorylase (MTAP) deletion - frequently co-occurring with loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) does not increase eADO levels but instead leads to intracellular accumulation of methylthioadenosine (MTA) reshaping methylation homeostasis and creating selective metabolic dependencies involving protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A). Recent evidence further indicates that nucleoside transport dynamics, particularly via equilibrative nucleoside transporter 1 (ENT1), regulate intracellular adenosine (iADO) availability in T cells and represent an additional regulatory layer linking extracellular purinergic signaling with intracellular immunometabolic control. Accordingly, we propose a functional immunometabolic convergence framework in which CD73-dependent extracellular eADO signaling, ENT1-regulated iADO handling, and MTAP loss-associated metabolic rewiring function as parallel yet cooperative processes that stabilize tumor immune escape.
Rosa et al. (Fri,) studied this question.