Mechanobiology of non-small cell lung cancer: bridging tumor mechanics and therapeutic strategies.
Non-small cell lung cancer (NSCLC) continues to account for the majority of lung cancer-related mortality, primarily due to disease progression and the development of resistance to conventional chemotherapy, targeted therapies, radiotherapy, and immunotherapy. While genetic and epigenetic alterations have been extensively studied, growing evidence indicates that these factors alone are insufficient to explain therapeutic failure. Recent advances highlight tumor mechanobiology as a critical regulator of cancer progression and treatment response. In NSCLC, progressive stiffening of the extracellular matrix (ECM), driven by aberrant collagen deposition, crosslinking, and cancer-associated fibroblast activation, generates biomechanical cues that profoundly influence tumor cell behavior. These mechanical signals are transduced through integrins and cytoskeletal networks, activating downstream pathways such as focal adhesion kinase, Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signaling, and the Hippo pathway effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Sustained activation of these pathways promotes epithelial-mesenchymal transition, stemness, and immune evasion, collectively contributing to therapy resistance and tumor aggressiveness. This review provides details of current evidence linking ECM stiffness-mediated mechanotransduction to therapeutic resistance in NSCLC. Furthermore, it discusses emerging therapeutic strategies aimed at targeting tumor mechanics, including ECM normalization, inhibition of mechanosensitive signaling nodes, and cancer-associated fibroblast modulation. By integrating biomechanical regulation with molecular signaling and therapeutic perspectives, this review underscores tumor mechanics as an underappreciated but clinically relevant determinant of treatment outcome. Targeting mechanobiology-driven resistance may offer novel opportunities to enhance therapeutic efficacy and improve clinical outcomes in patients with NSCLC.