Extracellular ATP accumulation in the tumor microenvironment drives immune evasion and adaptive resistance to immunotherapy through P2RY2 receptor signaling, which serves as the primary upstream trigger of COX-1/2-mediated PGE₂ production, and genetic or pharmacological disruption of P2RY2 eliminates both baseline and therapy-induced intratumoral PGE₂, restores antitumor T cell responses, and overcomes resistance to CAR-T, TCR-T, checkpoint blockade, and TIL therapies across diverse solid tumor types.

Extracellular ATP (eATP) accumulates substantially in the tumor microenvironment (TME) and rises further during immunotherapy. While canonically an immune-activating “danger” signal, eATP also promotes immunosuppression in tumors, thus far largely attributed to its metabolite, adenosine. Here, we identify direct eATP signaling through P2RY2 as a dominant, adenosine-independent mechanism of immune resistance. Specifically, eATP–P2RY2 signaling serves as the primary upstream driver of COX-1/2 upregulation and consequent accumulation of immunosuppressive PGE₂ in the TME, uncovering the long-sought TME-specific trigger of pathological COX–PGE₂ hyperactivation in solid tumors. Genetic deletion or pharmacologic inhibition of P2RY2 eliminates both baseline and therapy-induced intratumoral PGE₂, restores antitumor T cell responses, and reverses resistance to CAR-T, TCR-T, checkpoint blockade, and TIL therapies. Given that persistently elevated eATP is a hallmark of solid tumors, our work reveals a fundamental mechanism by which tumors hijack innate “danger” signaling to establish immune suppression and develop adaptive resistance to immunotherapy. These findings establish P2RY2 as a purinergic immune checkpoint with translational potential for combinatorial cancer immunotherapies.

HIGHLIGHTS

eATP in the TME drives baseline and therapy-induced immune evasion via P2RY2

eATP-P2RY2 signaling is the primary cause of PGE₂ accumulation in the TME

P2RY2 propels a feedback loop that enforces adaptive resistance to immunotherapies

P2RY2 blockade reprograms the TME and restores immunotherapy responsiveness