ATP is not always pro-inflammatory: rethinking purinergic signalling in cancer and autoimmunity

Extracellular adenosine 5'-triphosphate (ATP) has been recognized for many years as a prototypical danger signal that promotes inflammation primarily through activation of purinergic receptors, particularly P2X7. This framework has had a massive influence on how immunology, cancer biology, and autoimmunity are now conceived. Nonetheless, increasing experimental and clinical observations do not support the simple, unidimensional model of ATP as a pro-inflammatory mediator; instead, they suggest that, depending on the concentration, timing, receptor context, and cellular status, ATP may have strong immunosuppressive/tolerogenic effects. Prolonged ATP signalling has increasingly been implicated in immune effector fatigue during chronic inflammation, cancer, and sustained infection, which dampens down immune stimulation rather than augmenting it. In this narrative review, we critically examine published evidence supporting the context-dependent effects of extracellular ATP and discuss how receptor expression, ATP concentration, exposure duration, nucleotide metabolism, and cellular state may shape immune responses in cancer and autoimmune disease.