Piezo1 Activation Improves NSCLC Liver Metastasis Immunotherapy by Overriding Matrix Stiffness‐Mediated Bimodal PD‐L1/CXCL10 Regulation

Abstract Immunotherapy efficacy in NSCLC is significantly reduced upon liver metastasis due to profound alterations in the tumor microenvironment, characterized by the absence of cyclic mechanical stretch and increased extracellular matrix (ECM) stiffness. However, the mechanisms underlying the synergistic regulation of these two mechanical cues on the immunotherapy response in NSCLC cells remain poorly understood. In this study, it is demonstrated that both mechanical and biochemical activation of the mechanosensitive ion channel Piezo 1 induces nuclear translocation of YAP, thereby promoting an immunotherapy‐responsive tumor immune microenvironment (TIME) through enhanced expression of PD‐L1 and secretion of chemokine C‐X‐C ligand 10 (CXCL10, chemokine recruiting CD8 ⁺ T cells) in NSCLC cells. The mathematical modeling further reveals that cyclic stretch modulates the PD‐L1/CXCL10 response to ECM stiffness, shifting from a bimodal to a unimodal distribution. In a murine model of liver metastasis, the combination of Piezo 1 agonist with anti‐PD‐1 therapy significantly improves the immunotherapy response, as evidenced by elevated PD‐L1 levels and increased CD8 ⁺ T cell infiltration. These findings underscore the critical role of Piezo 1 in enhancing the immunotherapeutic response in NSCLC liver metastasis and highlight its potential as a therapeutic target.