Extracellular ATP-P2RY2 signaling drives intratumoral prostaglandin E2 accumulation and adaptive resistance to immunotherapy in solid tumors

Extracellular ATP (eATP) accumulates in the tumor microenvironment (TME), where its metabolite adenosine is implicated in promoting immunosuppressive pathways. We found that immunotherapy further increased eATP concentrations in the TME. eATP directly signaled through the purinergic receptor P2RY2 in tumor cells to suppress T cell function, independently of its metabolites. Mechanistically, eATP-P2RY2 signaling drove expression of cyclooxygenase (COX)-1 and COX-2 and downstream accumulation of prostaglandin E2 (PGE₂). Genetic deletion or pharmacologic inhibition of P2RY2 reduced baseline intratumoral PGE₂ and prevented therapy-induced PGE₂ accumulation, changed the TME immune infiltrate, restored antitumor T cell responses, and overcame resistance to immune checkpoint blockade, CAR-T, and TCR-T therapies. A P2RY2 antagonist monoclonal antibody recapitulated the in vivo therapeutic benefit and enhanced human autologous tumor-infiltrating lymphocyte responses against matched tumor cells ex vivo . Thus, persistent eATP-P2RY2 signaling in the TME drives a PGE₂-mediated immunosuppressive circuit that operates at baseline and is further amplified during immunotherapy, driving adaptive resistance.