Mechanobiology of cancer-associated thrombosis: from molecular mechanisms to therapeutic innovation.

Cancer-associated thrombosis (CAT) is the second leading cause of death in cancer patients, with venous thromboembolism affecting 20–30% of cases. While conventional models emphasize biochemical mediators such as tissue factor (TF) and inflammatory cytokines, they incompletely explain the spatial heterogeneity and therapeutic resistance of CAT. This review presents a mechanobiology-centered framework that integrates physical forces—including aberrant hemodynamics, elevated interstitial pressure, and matrix stiffening—with cellular mechanotransduction to explain thrombogenesis in malignancy. We examine how tumor-induced mechanical cues activate PIEZO1 channels, integrin-focal adhesion signaling, and YAP/TAZ transcriptional programs, collectively driving TF expression, extracellular vesicle release, platelet hyperreactivity, and neutrophil extracellular trap formation. Red blood cells (RBCs) emerge as underappreciated mechanobiological contributors through rheology-dependent and phosphatidylserine-mediated mechanisms. Advanced microfluidic platforms recapitulating tumor-specific shear conditions enable mechanistic dissection and compound screening under physiologically relevant flow. Therapeutic strategies targeting upstream mechanosensitive pathways—including PIEZO1 modulation, YAP/TAZ-TEAD inhibition, and membrane tension control—offer potential to attenuate prothrombotic outputs while preserving hemostasis. Integration of mechanobiological biomarkers with machine-learning risk models may enhance CAT prediction beyond current clinical scores. This multi-scale perspective bridges molecular mechanosensors to tissue-level hemodynamics, establishing a foundation for precision thromboprophylaxis informed by the mechanical phenotype of individual tumors.