The review discusses the role of extracellular matrix (ECM) cues in regulating mechanosensing and mechanotransduction in cancer cells. It highlights how cells not only react to mechanical cues from the ECM but can also manipulate these cues, affecting downstream processes in both physiological and pathological contexts. The stiffness and shear flow of ECM in normal and cancerous tissues differ significantly, ranging from 500 Pa to 48 kPa and 0.1–1 dyn/cm² to 1–10 dyn/cm², respectively. The review explores the complex interactions between ECM and cancer cells, emphasizing the importance of these interactions in various diseases, particularly cancer. It also discusses the development of ECM-mimicking biomaterials and their potential in understanding and treating cancer. The review covers the mechanisms of mechanotransduction, including tensile force, hydrostatic pressure, fluid shear stress, and the mTOR-FAK signaling axis, and their impact on cell behavior. Additionally, it examines the plasticity of cells in response to ECM stiffness and the role of metaplasia in carcinogenesis. The review concludes by discussing the importance of biophysical properties in controlling cancer cell plasticity and the challenges in manipulating ECM without altering its stiffness.The review discusses the role of extracellular matrix (ECM) cues in regulating mechanosensing and mechanotransduction in cancer cells. It highlights how cells not only react to mechanical cues from the ECM but can also manipulate these cues, affecting downstream processes in both physiological and pathological contexts. The stiffness and shear flow of ECM in normal and cancerous tissues differ significantly, ranging from 500 Pa to 48 kPa and 0.1–1 dyn/cm² to 1–10 dyn/cm², respectively. The review explores the complex interactions between ECM and cancer cells, emphasizing the importance of these interactions in various diseases, particularly cancer. It also discusses the development of ECM-mimicking biomaterials and their potential in understanding and treating cancer. The review covers the mechanisms of mechanotransduction, including tensile force, hydrostatic pressure, fluid shear stress, and the mTOR-FAK signaling axis, and their impact on cell behavior. Additionally, it examines the plasticity of cells in response to ECM stiffness and the role of metaplasia in carcinogenesis. The review concludes by discussing the importance of biophysical properties in controlling cancer cell plasticity and the challenges in manipulating ECM without altering its stiffness.