P2RY2 fuelled by eATP drives cancer immune evasion and therapy resistance

In this study, we identify P2RY2 as a pivotal upstream driver of both PGE2 accumulation and B7-H3 upregulation in the TME. This process is fuelled by extracellular ATP (eATP), a cognate ligand for P2RY2 that is commonly and markedly elevated in the TME and rises further under immunotherapies. Genetic or pharmacological disruption of P2RY2 substantially reduces intratumoural PGE2 and B7-H3, increasing T cell infiltration, effector functions, proliferation, and persistence within the TME. Consequently, targeting P2RY2 substantially improves the efficacy of TCR-engineered T cells, CAR-T cells, and immune checkpoint blockade (ICB) in multiple syngeneic and humanized mouse tumour models, and potentiates patient-derived tumour-infiltrating lymphocytes (TILs) against paired primary tumour cells. By establishing P2RY2 as the crucial link between eATP and tumour-induced immunosuppression, our study reveals how a receptor typically associated with innate “danger” signalling can be hijacked to undermine adaptive immunity, thereby providing a promising therapeutic avenue to overcome a common immune resistance mechanism in cancer and advance T cell–based cancer therapies.