Fig. 2. Increased ECM stiffness mediates the aggressive phenotype of cancer cells.

Elevated ECM stiffness induces morphological changes in tumor cells, primarily in the form of pseudopodia formation, expanded spreading areas, and enhanced cell adhesion. These changes promote cancer cell proliferation. Additionally, an increase in ECM stiffness drives metabolic reprogramming in cancer cells. Furthermore, EMT facilitated by ECM stiffness contributes to distant metastasis through a sequence of stages. Notably, increased ECM stiffness creates a physical barrier in the TME, which enhances drug efflux, reduces immune cell cytotoxicity, and impedes the infiltration of oxygen, drugs, and immune cells.