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Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor

Jinjia Zhang,Junhong Li,Yongqiang Hou,Yao Lin,Hao Zhao,Yiran Shi,Kaiyun Chen,Cheng Nian,Jiayu Tang,Lei Pan,Yunzhi Xing,Huan Gao,Bingying Yang,Zengfang Song,Yao Cheng,Yue Liu,Min Sun,Yueyue Linghu,Jiaxin Li,Haitao Huang,Zhangjian Lai,Zhien Zhou,Zifeng Li,Xiufeng Sun,Qinghua Chen,Dongxue Su,Wengang Li,Zhihai Peng,Pingguo Liu,Wei Chen,Hongling Huang,Yixin Chen,Bailong Xiao,Lilin Ye,Lanfen Chen,Dawang Zhou

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.