Cancer-associated fibroblasts -derived Tenascin-C activates the Hippo/TAZ pathway to suppress ferroptosis and confer cisplatin resistance in esophageal cancer

This study aims to investigate the mechanistic role of fibronectin (TNC) secreted by cancer-associated fibroblasts (CAFs) and its impact on cisplatin (DDP) sensitivity in esophageal squamous cell carcinoma (ESCC). Through in vitro cell experiments and analyses of clinical specimens, we observed that elevated levels of CAF-derived TNC significantly downregulate TAZ (WWTR1) expression in cancer cells and inhibit ferroptosis, thereby contributing to increased resistance to cisplatin. Mechanistically, TNC exerts its effects by activating the Hippo signaling pathway, which suppresses TAZ expression, reduces intracellular iron accumulation, and decreases the expression of ferroptosis-related proteins, ultimately diminishing drug sensitivity. Intervention experiments demonstrated that knocking down TNC or restoring TAZ expression enhances ferroptosis and augments cisplatin-induced cytotoxicity. Clinically, high expression levels of FAP and TNC are correlated with adverse pathological features, indicating that the TNC/TAZ axis may serve as a potential biomarker and therapeutic target for modulating chemosensitivity in ESCC. Our findings reveal a critical role for CAF-derived TNC in regulating ferroptosis and chemoresistance, providing new insights into therapeutic strategies aimed at improving treatment outcomes for ESCC.