Tumor under forces: biophysical remodeling of tumor microenvironment and associated therapeutic opportunities

Tumors progress within a mechanically dynamic tumor microenvironment (TME), where extracellular matrix (ECM) stiffening, solid stress, and elevated interstitial fluid pressure remodel tumor cell and tumor-associated cell behavior. This TME-related mechanical remodeling often leads to tumor progression, metastasis and therapy resistance. In this review, we highlight recent advances in tumor mechanobiology, emphasizing how biophysical forces generated by cross-talk between tumor cells and tumor-associated cells precisely drive TME remodeling-ECM stiffening, hypoxia, leaky vasculature, invasion and therapy resistance-to support cancer progression. We discuss emerging interventions for selective tumor targeting that exploit the mechanical properties of the TME and biomechanical vulnerabilities of tumors and tumor-associated cells. Finally, this review explores the potential to leverage mechanobiological insights into the TME using New Approach Methodologies (NAMs), such as 3D bioprinted models and organ-on-chip platforms, coupled with AI-powered image analysis and modeling, to enable personalized cancer diagnosis and treatment.