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Figure 1. Mechanical stress in the tumor microenvironment and convergence on drug resistance. Schematic of shear stress, matrix stiffness, and compressive stress, and their convergence on cytoskeletal responses. Mechanical signals are sensed by mechanosensitive ion channels (PIEZO1, TRPV4, TRPM7) and membrane proteins (Cav-1, GPCR, Integrin), and converge on coordinated remodeling of microfilaments, microtubules, and intermediate filaments, ultimately promoting drug resistance. (A) Shear stress: High shear occurs at tumor margins and in narrowed vessels, while low shear is present in the tumor core or stagnation areas. Interstitial fluid shear in the interstitial space and abnormal vascular leakage are also depicted; (B) ECM stiffness: CAF-mediated ECM crosslinking leads to denser ECM in the tumor core compared to the edge, and loose ECM in normal tissue. Cytoskeletal responses include actin forming a contractile network and microtubules providing flexible support; (C) Compressive stress: ECM overcrowding and vascular compression result in higher pressure in the tumor core (30-50 kPa) than at the edge (10-20 kPa) or in normal tissue (< 5 kPa). Cytoskeletal responses involve actin resisting compression, microtubules maintaining transport, intermediate filaments protecting the nucleus, and nuclear fiber layers maintaining nuclear shape. Cav-1: Caveolin-1; CAF: cancer-associated fibroblast; ECM: extracellular matrix; GPCR: G protein-coupled receptor; PIEZO1: piezo type mechanosensitive ion channel component 1; TRPV4: transient receptor potential vanilloid 4; TRPM7: transient receptor potential melastatin 7.