Metabolic reprogramming and intracellular ATP homeostasis in immunity

The purine molecule ATP plays a crucial role in essential cellular functions, including energy transfer and extracellular signaling. It also serves as a precursor for the structural components of nucleic acids, including DNA and RNA, as well as for cyclic AMP and various cofactors. ATP is continuously degraded in cells and in extracellular space, leading to the sequential formation of ADP, AMP, adenosine, inosine, and hypoxanthine. ATP degradation is counterbalanced by the coordinated action of de novo biosynthetic pathways and salvage mechanisms, which generate inosine-5'-monophosphate (IMP), a precursor of AMP, which is subsequently converted into ATP. The synthesis and overall metabolism of ATP is closely linked to immune cell function, and dysregulation of these metabolic pathways can lead to immunodeficiency or worsen inflammatory diseases. Several approved drugs targeting ATP metabolism, including methotrexate, azathioprine, and allopurinol, are widely used to modulate immune system activity in the treatment of cancer, autoimmune diseases, and in gout. Here, we highlight the role of intracellular ATP homeostasis in coordinating bioenergetics and metabolism of immune cells. We also discuss inherited and acquired disorders that result in compromised ATP metabolism and impact immunity, as well as reviewing novel therapeutic approaches to target purinergic pathways in immunodeficiency and inflammatory diseases.