P2RX7 programs checkpoint-responsive exhausted CD8+ T cell states through a KLF3 metabolic circuit

Abstract Checkpoint-responsive exhausted CD8 + T cells sustain immunity during chronic infection and cancer, but the tissue-derived signals that preserve these cells remain poorly defined. Here, we identify extracellular ATP sensing through P2RX7 as a microenvironmental circuit that maintains progenitor exhausted (T PEX ) and tissue-resident exhausted (TR TEX ) CD8 + T cells. P2RX7 was enriched in T PEX and TR TEX cells and was required cell-intrinsically to preserve their abundance, diversity, and developmental competence during chronic viral infection. Loss of P2RX7 restricted early progenitor trajectories and induced mitochondrial dysfunction, lipid peroxidation, and terminal exhaustion-associated phenotypes. Mechanistically, P2RX7-dependent Ca 2+ influx activated NFAT/AP-1 signaling, which induced KLF3 to promote mitochondrial fitness, subset development, and persistence of T PEX and TR TEX cells. P2RX7 also supported CD8 + T cell expansion after PD-1 blockade, whereas pharmacologic P2RX7 activation enhanced antitumor immunity in preclinical models. These findings define an extracellular ATP-P2RX7-KLF3 program that couples tissue damage sensing to metabolic adaptation and persistence of checkpoint-responsive exhausted CD8 + T cells.