Extracellular Matrix Mechanics in Cancer: Mechanotransduction, Cellular Phenotype, and Therapeutic Resistance

Abstract

Abnormal extracellular matrix (ECM) stiffening emerges chiefly from enhanced matrix deposition and remodelling by cancer cells and cancer-associated fibroblasts. This biomechanical alteration activates mechanosensitive pathways, principally through integrin-mediated adhesion complexes, which transmit external stiffness cues into intracellular biochemical signals via focal adhesions and the cytoskeleton. A key consequence of this mechanotransduction is the regulation of potent transcription factors such as Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), β-catenin, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), each of which modulates gene networks involved in proliferation, migration, and cellular plasticity. The amplification of these signalling events alters cell fate and encourages aggressive phenotypes by promoting epithelial-to-mesenchymal transition (EMT), invasiveness, and survival. Moreover, ECM stiffening leads to resistance to conventional therapies by reorganising gene expression profiles that bolster DNA repair and evasion of apoptosis, while simultaneously impairing drug delivery through increased tissue density and vascular collapse. This review highlights mechanotransduction pathways that connect extracellular matrix stiffness with cancer cell phenotypic alterations and the development of therapeutic resistance. As such, the mechanics of the ECM act not only as a physical scaffold but also as a dynamic regulator of the malignant cancer-cell phenotype and therapeutic outcomes. The review further evaluates emerging therapeutic strategies targeting ECM synthesis and cross-linking, cancer-associated fibroblasts (CAFs), integrin-focal adhesion signalling, and downstream mechanotransduction pathways such as YAP/TAZ and β-catenin, while emphasising the limitations of current ECM-targeted approaches and the need for biomarker-guided combination therapies. The significance of this review lies in highlighting ECM stiffness-mediated mechanotransduction as a potentially actionable mechanism linking the physical tumour microenvironment (TME) to cancer progression and therapeutic resistance, thereby providing a rationale for developing novel therapies that target both tumour cells and their mechanical microenvironment.