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The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E (PGE) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE signalling in CAR T cells may enhance their activity in PGE-rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE receptors EP2 and EP4 (EP2EP4) by CRISPR-Cas9 engineering. EP2EP4 CAR T cells expanded unabatedly in the presence of PGE. Further, they effectively controlled syngeneic and human xenograft tumour models in vivo, which was accompanied by intratumoural accumulation and persistence of modified T cells. Improved anti-tumour activity was also observed against patient-derived tumour samples from patients with pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC) and neuroendocrine (NET) cancer. Our data uncovers the detrimental impact of PGE-mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.