Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8⁺ T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8⁺ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8⁺ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8⁺ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8⁺ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8⁺ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.

细胞外基质 (ECM) 结构和硬度的改变是癌症的标志。 ECM 的生物力学特性是否影响肿瘤反应性 CD8 ⁺ T 细胞的功能仍然很大程度上未知。在这里，我们揭示了转录因子（TF）Osr2 整合了生物力学信号并促进肿瘤反应性 CD8 ⁺ T 细胞的终末耗竭。 Osr2 的表达是通过耦合 T 细胞受体 (TCR) 信号传导和 Piezo1/钙/CREB ​​轴介导的生物力学应激在最终耗尽的肿瘤特异性 CD8 ^{+ T 细胞亚群中选择性诱导的。一致地，Osr2 的耗竭减轻了肿瘤特异性 CD8 +} T 细胞或 CAR-T 细胞的耗竭，而强迫 Osr2 表达则加剧了实体瘤模型中的耗竭。从机制上讲，Osr2 招募 HDAC3 来重新连接表观遗传程序，以抑制细胞毒性基因表达并促进 CD8 ⁺ T 细胞耗竭。因此，我们的结果揭示了 Osr2 作为生物力学检查点的功能，可加剧 CD8 ⁺ T 细胞耗竭，并可用于增强癌症免疫治疗。