Extracellular matrix stiffness and mechanotransduction in cancer drug resistance

Extracellular matrix (ECM) is a key component in the tumor microenvironment (TME). The stiffened ECM not only acts as a barrier to prevent drug delivery but also facilitates tumor progression via activating cell membrane receptors and mechanical sensors, such as Piezo1 ion channels, integrins, and Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). Accumulating evidence suggests that stiffer ECM and aberrant mechanotransduction contribute to treatment resistance. Targeting ECM stiffness and mechanotransduction pathways and restoring mechanical abnormalities in the TME provide opportunities for the rational design of combination therapies, especially in drug-resistant tumors. Therefore, elucidating how ECM stiffness regulates cancer drug resistance will facilitate the development of new therapeutic strategies for improving patient outcomes. In this review, we summarize the key factors that regulate ECM stiffness during tumor progression. We comprehensively analyze the multi-faceted mechanisms of ECM stiffness in cancer therapy resistance and discuss potential strategies that target ECM components and downstream signaling pathways for improving treatment efficacy. This comprehensive review will enhance the understanding of the functional roles of ECM stiffness and mechanotransduction in cancer drug resistance, providing basic knowledge for exploring novel therapeutic strategies.