Expansion of antigen-experienced CD8⁺ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer¹. Interleukin-2 (IL-2) acts as a key regulator of CD8⁺ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability^2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE₂), a known negative regulator of immune response in the tumour microenvironment^4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8⁺ TILs via the PGE₂ receptors EP2 and EP4. Mechanistically, PGE₂ inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ_c chain, resulting in defective assembly of IL-2Rβ–IL2Rγ_c membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE₂ signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE₂ in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.

经历过抗原的 CD8 ⁺ T 细胞的扩增对于癌症患者肿瘤浸润淋巴细胞 (TIL) 过继性细胞疗法 (ACT) 的成功至关重要¹。白细胞介素-2 (IL-2) 通过促进扩增和细胞毒性能力，充当 CD8 ⁺细胞毒性 T 淋巴细胞功能的关键调节剂^2,3。因此，必须了解肿瘤微环境中 IL-2 传感的机制障碍，以实施重振 IL-2 反应性和 T 细胞抗肿瘤反应的策略。在此，我们报告前列腺素 E2 (PGE ₂ ) 是肿瘤微环境中已知的免疫反应负调节剂^{4,5 ，在患者的肿瘤组织中以高浓度存在，并通过以下方式导致人类 CD8 +} TIL中的 IL-2 感应受损：PGE ₂受体EP2和EP4。从机制上讲，PGE ₂通过下调 IL-2Rγ _c链来抑制 TIL 中的 IL-2 感应，导致 IL-2Rβ–IL2Rγ _c膜二聚体的组装缺陷。这导致 IL-2–mTOR 适应性受损和 PGC1α 转录抑制，导致肿瘤反应性 TIL 中的氧化应激和铁死亡。在 ACT 的 TIL 扩增过程中抑制 PGE ₂ 信号转导至 EP2 和 EP4 会导致 IL-2 感应增加，从而增强肿瘤反应性 TIL 的增殖，并在细胞转移到体内后增强肿瘤控制。我们的研究揭示了肿瘤微环境中PGE ₂介导的人类 TIL 损伤的基本特征。这些发现对癌症免疫疗法和细胞疗法具有治疗意义，并且能够开发靶向策略来增强 TIL 中的 IL-2 感应和放大 IL-2 反应，从而促进效应 T 细胞的扩增，增强治疗潜力。