biostudies-literatureLacher SBEuropean Research Council417-425https://www.ebi.ac.uk/biostudies/studies/S-EPMC11078747biostudies-literatureUnknown629(8011)Cancer-specific TCF1⁺ stem-like CD8⁺ T cells can drive protective anticancer immunity through expansion and effector cell differentiation^1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies^2,5-9 can promote anticancer responses through TCF1⁺ stem-like CD8⁺ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1⁺CD8⁺ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE₂) restricts the proliferative expansion and effector differentiation of TCF1⁺CD8⁺ T cells within tumours, which promotes cancer immune escape. PGE₂ does not affect the priming of TCF1⁺CD8⁺ T cells in draining lymph nodes. PGE₂ acts through EP₂ and EP₄ (EP₂/EP₄) receptor signalling in CD8⁺ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1⁺ tumour-infiltrating CD8⁺ T lymphocytes (TILs). Ablation of EP₂/EP₄ signalling in cancer-specific CD8⁺ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE₂-mediated inhibition of TCF1⁺ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1⁺ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE₂-EP₂/EP₄ axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.NaturePGE₂ limits effector expansion of tumour-infiltrating stem-like CD8⁺ T cells.PMC11078747756017101100460101124203Oner ABayerl FMajed LBriukhovetska DStock SDorr JGregor LLacher SBSpranger NMichaelides SKnolle PADangaj Laniti DBusch DHBottcher JPHirschberger APedde AMRudolph TJBuchholz VRZehn DHonninger JLesch SRamsauer LKobold Sde Almeida GPFertig LGrimm AJMorotti MJarosch SMeiser PfalsePGE₂ limits effector expansion of tumour-infiltrating stem-like CD8⁺ T cells.Cancer-specific TCF1⁺ stem-like CD8⁺ T cells can drive protective anticancer immunity through expansion and effector cell differentiation^1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies^2,5-9 can promote anticancer responses through TCF1⁺ stem-like CD8⁺ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1⁺CD8⁺ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE₂) restricts the proliferative expansion and effector differentiation of TCF1⁺CD8⁺ T cells within tumours, which promotes cancer immune escape. PGE₂ does not affect the priming of TCF1⁺CD8⁺ T cells in draining lymph nodes. PGE₂ acts through EP₂ and EP₄ (EP₂/EP₄) receptor signalling in CD8⁺ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1⁺ tumour-infiltrating CD8⁺ T lymphocytes (TILs). Ablation of EP₂/EP₄ signalling in cancer-specific CD8⁺ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE₂-mediated inhibition of TCF1⁺ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1⁺ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE₂-EP₂/EP₄ axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.2024-01-01T00:00:00Z2024 May2026-06-03T06:51:23.839Z2026-04-25T03:22:12.913ZS-EPMC110787473865874810.1038/s41586-024-07254-x