Cancer-specific TCF1⁺ stem-like CD8⁺ T cells can drive protective anticancer immunity through expansion and effector cell differentiation^1,2,3,4; however, this response is dysfunctional in tumours. Current cancer immunotherapies^2,5,6,7,8,9 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.

癌症特异性 TCF1 ⁺干细胞样 CD8 ⁺ T 细胞可以通过扩增和效应细胞分化来驱动保护性抗癌免疫^1,2,3,4；然而，这种反应在肿瘤中却不起作用。目前的癌症免疫疗法^2,5,6,7,8,9可以通过 TCF1 ⁺干细胞样 CD8 ⁺ T 细胞在一些但不是所有患者中促进抗癌反应。这种变异表明目前限制 TCF1 ⁺ CD8 ⁺ T 细胞介导的抗癌免疫的机制不明确。在这里，我们证明肿瘤源性前列腺素 E2 (PGE _{2 ) 限制肿瘤内 TCF1} ⁺ CD8 ⁺ T 细胞的增殖扩张和效应分化，从而促进癌症免疫逃逸。 PGE ₂不影响引流淋巴结中TCF1 ⁺ CD8 ⁺ T 细胞的启动。 PGE ₂通过CD8 ⁺ T 细胞中的EP ₂和 EP ₄ (EP ₂ /EP ₄ ) 受体信号传导发挥作用，限制源自 TCF1 ⁺肿瘤浸润 CD8 ⁺ T 淋巴细胞 (TIL)的早期和晚期效应 T 细胞群的肿瘤内生成）。消除癌症特异性 CD8 ⁺ T 细胞中的 EP ₂ /EP ₄信号传导可挽救其在肿瘤内的扩增和效应分化，并导致多种小鼠癌症模型中的肿瘤消除。从机制上讲，白介素 2 (IL-2) 信号通路的抑制是 PGE ₂介导的 TCF1 ⁺ TIL 反应抑制的基础。总而言之，我们发现了一种限制 TCF1 ⁺ TIL 的 IL-2 反应性并阻止源自这些细胞的抗癌 T 细胞反应的关键机制。本研究确定 PGE ₂ –EP ₂ /EP ₄轴作为恢复抗癌 TIL 中 IL-2 反应性的分子靶点，从而实现癌症免疫控制。