Abstract

Adoptive T cell therapy (ACT) remains limited in solid tumors by poor T cell persistence within the metabolically hostile tumor microenvironment (TME). Although IL-9-producing CD8+T cells (Tc9) consistently demonstrate superior antitumor efficacy compared with conventional Tc1 cells, the selective pressures that shape their functional advantage remain unclear. Here, we show that effective ACT-mediated tumor control is accompanied by a marked increase in intratumoral extracellular ATP (eATP), representing a common metabolic consequence of tumor cell destruction. Despite comparable ATP accumulation following Tc1 or Tc9 treatment, these subsets exhibit strikingly distinct responses to ATP stress. Tc1 cells are highly susceptible to ATP-induced apoptosis, whereas Tc9 cells display intrinsic resistance, resulting in superior in vivo persistence. Mechanistically, Tc9 cells actively convert ATP signaling into enhanced mitochondrial fitness, characterized by increased oxidative phosphorylation and spare respiratory capacity. ATP exposure further drives Tc9 cells toward a tissue-resident memory (TRM) phenotype through activation of the TGF-β signaling axis. Transcriptomic and molecular analyses reveal that purinergic signaling pathways, including elevated expression of the ATP receptor P2RX7, are intrinsically enriched in Tc9 cells and are further amplified upon ATP stimulation. Collectively, our findings identify extracellular ATP as a metabolic lineage selection signal in ACT, demonstrating that ATP stress preferentially stabilizes metabolically resilient Tc9 cells by linking purinergic sensing to mitochondrial remodeling and TRM programming, thereby providing a conceptual basis for enhancing the persistence and efficacy of engineered T cell therapies in solid tumors.