Mechanobiology of the tumor microenvironment: a review of therapeutic interactions and in vitro elasticity measurement techniques.

The stiffness of the extracellular matrix (ECM) regulates cellular behavior, influencing tumor progression and therapeutic resistance. In cancer, aberrant ECM stiffening can reduce immune cell infiltration and treatment efficacy, which can in turn alter the tumor microenvironment. Here, we review the role of ECM stiffness in cancer biology and its relevance to matrix-targeted therapies and biomaterial design. We discuss three-dimensional (3D) in vitro models that mimic native tissues and the bidirectional interactions between ECM mechanics and therapeutic interventions. A comparative analysis of measurement modalities is presented for characterizing complex 3D environments, including shear-wave-based techniques such as optical and ultrasound elastography and non-shear-wave-based approaches such as atomic force microscopy and rheology. Future directions include developing matrix-modulating therapies, integrating elasticity sensors into microfluidic devices for higher throughputs and physiological relevance, and applying machine learning to interpret heterogeneous mechanical properties. Collectively, these engineering and biological advances highlight ECM stiffness as a tractable target and open translational opportunities for predictive modeling, diagnostic platforms, and matrix-directed therapies to improve cancer treatment.