The dynamic physical niche: shaping cancer progression and therapy response

The tumor microenvironment (TME) constitutes a distinct biophysical niche that dictates malignancy, extending far beyond a mere structural scaffold. This review outlines the aberrant mechanical properties defining this niche, including solid stress, interstitial fluid pressure (IFP), matrix stiffness, viscoelasticity and microstructure. We describe the mechanotransduction axes from cell-surface mechanosensors and ion channels to the ‘molecular motor-clutch’ machinery that transduce physical cues into nuclear deformation. Furthermore, we discuss the reciprocal crosstalks among cancer cells, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs) in restructuring the physical microenvironment. This dynamic remodeling establishes a feed-forward mechanical circuit that sustains proliferation, metastasis, and therapeutic resistance in cancer. Finally, we propose that targeting these biophysical abnormalities to restore mechanical homeostasis represents key therapeutic vulnerabilities for cancer progression.