Cancer cells subvert immune surveillance through inhibition of T cell effector function. Elucidation of the mechanism of T cell dysfunction is therefore central to cancer immunotherapy. Here, we report that dual specificity phosphatase 2 (DUSP2; also known as phosphatase of activated cells 1, PAC1) acts as an immune checkpoint in T cell antitumor immunity. PAC1 is selectively upregulated in exhausted tumor-infiltrating lymphocytes and is associated with poor prognosis of patients with cancer. PAC1^hi effector T cells lose their proliferative and effector capacities and convert into exhausted T cells. Deletion of PAC1 enhances immune responses and reduces cancer susceptibility in mice. Through activation of EGR1, excessive reactive oxygen species in the tumor microenvironment induce expression of PAC1, which recruits the Mi-2β nucleosome-remodeling and histone-deacetylase complex, eventually leading to chromatin remodeling of effector T cells. Our study demonstrates that PAC1 is an epigenetic immune regulator and highlights the importance of targeting PAC1 in cancer immunotherapy.

癌细胞通过抑制 T 细胞效应功能破坏免疫监视。因此，阐明 T 细胞功能障碍的机制是癌症免疫治疗的核心。在这里，我们报告了双特异性磷酸酶 2（DUSP2；也称为活化细胞磷酸酶 1，PAC1）在 T 细胞抗肿瘤免疫中充当免疫检查点。PAC1 在耗尽的肿瘤浸润淋巴细胞中选择性上调，并且与癌症患者的不良预后相关。PAC1^嗨效应 T 细胞失去其增殖和效应能力并转化为耗尽的 T 细胞。PAC1 的缺失增强了免疫反应并降低了小鼠的癌症易感性。通过激活 EGR1，肿瘤微环境中过量的活性氧诱导 PAC1 的表达，从而募集 Mi-2β 核小体重塑和组蛋白-脱乙酰酶复合物，最终导致效应 T 细胞的染色质重塑。我们的研究表明 PAC1 是一种表观遗传免疫调节剂，并强调了靶向 PAC1 在癌症免疫治疗中的重要性。