The killing function of cytotoxic T cells can be enhanced biochemically. Here we show that blocking the mechanical sensor PIEZO1 in T cells strengthens their traction forces and augments their cytotoxicity against tumour cells. By leveraging cytotoxic T cells collected from tumour models in mice and from patients with cancers, we show that PIEZO1 upregulates the transcriptional factor GRHL3, which in turn induces the expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin, causing its downregulation and rearrangement, which depresses traction forces in the T cells. In mice with tumours, the injection of cytotoxic T cells collected from the animals and treated with a PIEZO1 antagonist promoted their infiltration into the tumour and attenuated tumour growth. As an immunomechanical regulator, PIEZO1 could be targeted to enhance the outcomes of cancer immunotherapies.

可以通过生化手段增强细胞毒性T细胞的杀伤功能。在这里，我们证明阻断 T 细胞中的机械传感器 PIEZO1 会增强它们的牵引力并增强它们对肿瘤细胞的细胞毒性。通过利用从小鼠肿瘤模型和癌症患者收集的细胞毒性 T 细胞，我们发现 PIEZO1 上调转录因子 GRHL3，进而诱导 E3 泛素连接酶 RNF114 的表达。 RNF114 与丝状肌动蛋白结合，导致其下调和重排，从而抑制 T 细胞的牵引力。在患有肿瘤的小鼠中，注射从动物身上收集并用 PIEZO1 拮抗剂处理的细胞毒性 T 细胞可以促进它们浸润到肿瘤中并减弱肿瘤生长。作为一种免疫机械调节剂，PIEZO1 可以靶向增强癌症免疫疗法的效果。