GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE289nnn/GSE289055/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE289055GEOGSEfalseP2RY2 fuelled by eATP drives cancer immune evasion and therapy resistanceIn 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.2026/07/07GSE289055GSM8782700GSM8782689GSM8782688GSM8782699GSM8782685GSM8782696GSM8782684GSM8782695GSM8782687GSM8782698GSM8782697GSM8782686GSM8782692GSM8782691GSM8782694GSM8782683GSM8782693GSM878269024676289055Homo sapiens[42392075]