Adenosine signals an imbalance between activity and supply in privileged cells

Extracellular adenosine (e-Ado) is a critical signaling molecule, yet its origin beyond energy stress and inflammation is underexplored. Herein, we propose that Ado is ubiquitously generated in the S-adenosylmethionine transmethylation pathway and integrate this source with the concept of cellular privilege in nutrient acquisition. In this model, less privileged cells convert Ado to adenosine monophosphate (AMP) under nutrient scarcity, activating AMP-activated protein kinase, while privileged cells release Ado to signal for resources. We define Ado as a sensor of the balance between cellular activity, reflected in methylation, and nutrient supply, reflected in ATP recycling. This framework redefines Ado's role in immunity, brain function, and aging and highlights transmethylation-derived Ado as a key factor in the tumor microenvironment and immunotherapeutic strategies.