Abstract

Mechanical properties are directly related to the efficacy of tumor chemotherapy. • Atomic force microscopy can well quantify the mechanical properties of tumors. • Regulating ECM stiffness through YAP1/BCl2/Bax to modulate the efficacy of cisplatin in lung cancer. Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related deaths worldwide, and cisplatin (DDP) resistance severely limits the efficacy of first-line chemotherapy. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors, yet how it modulates chemosensitivity remains unclear. This study demonstrates that matrix stiffness activates the mechanosensor YAP1 in lung adenocarcinoma, which in turn establishes an apoptosis-refractory state by upregulating Bcl2 and downregulating Bax. Functional experiments establish the YAP1–Bax axis as the core pathway, while clinical correlation analysis reveals that YAP1 expression significantly predicts poor post-chemotherapy survival. Our findings reveal a mechanism by which mechanical cues desensitize mitochondrial apoptosis through YAP1-driven transcriptional reprogramming, providing both new insights into chemoresistance mechanisms and a potential biomarker for treatment response.