Mechanobiology of Tumor Invasion: Combining Biomechanical Knowledge into Cancer Treatments

Abstract

Genetic alterations and biochemical signaling are central to malignant transformation; however, biomechanical cues within the tumor microenvironment (TME) also shape tumor behavior and treatment response. This narrative review critically evaluates how extracellular matrix (ECM) stiffness, solid stress, interstitial fluid pressure, and fluid shear stress influence invasion, metastasis, and therapeutic resistance. These cues engage integrin-focal adhesion kinase (FAK) signaling, RhoA-ROCK-dependent cytoskeletal tension, and the mechanosensitive transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). We discuss how these routes interact with Wnt/β-catenin and transforming growth factor-β (TGF-β)/SMAD signaling, and how their effects depend on tumor type, matrix architecture, and disease stage. Rather than treating stiffness, solid stress, and fluid pressure as interchangeable, we compare their biological consequences and measurement approaches. We also assess the strengths and limitations of microfluidic and organ-on-chip platforms, elastography, and ex vivo nanomechanical assays. ECM-directed remodeling, mechanical decompression, and pathway inhibition offer complementary treatment strategies, but variable clinical efficacy, off-target effects, and biomarker standardization remain significant barriers. Integrating spatially resolved biomechanical measurements with molecular profiling may improve patient stratification and guide rational combination therapies.