Osr2 functions as a mechanical checkpoint to augment CD8+ T cell exhaustion [Osr2OE_vs_Vector_CutnTag_CD8]

The alteration in extracellular matrix (ECM) architecture and stiffness becomes one of the hallmarks of cancer. Whether the mechanical property of ECM contributes to the functionality of CD8+ T cells, a key component of anti-tumor response, remains largely unknown. Here we report that mechanical stress drives T cell exhaustion program via Osr2, a transcription factor that had been poorly investigated in T cells. Osr2 is highly and selectively induced in CD8+ T cells when encountering stiff matrix or mechanical force signaling (MFS). Integrated genetic and multi-omics analyses reveals that Osr2 is enriched in the terminal exhausted tumor infiltrating lymphocytes and its expression is modulated by the combined TCR and MFS mediated by Piezo1/Calcium/CREB axis. Importantly, depletion of Piezo1 or Osr2 alleviates T cell exhaustion, which is associated with enhanced anti-tumor immunity mediated by antigen specific T cells or CAR-T cells in solid tumor models. On the contrary, forced Osr2 expression in CD8+ T cells augment their exhaustion and dampens tumor control. In agreement with these observations, high Osr2 expression is correlated with poor prognosis in multiple human malignancies. Mechanistically, Osr2 recruits HDAC3, which in turn establishes epigenetic reprogramming to suppress cytotoxic genes expression and to promote CD8+T cell exhaustion. Thus, our results unravel a mechanical signaling cascade centered by Osr2 that serves as a key driver for CD8+ T cell exhaustion and suggest that mechanical checkpoints could be promising targets for cancer immunotherapy.