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.