The mechanics of anoikis resistance in cancer

Metastatic cancer cells display a remarkable ability to resist the mechanical and biochemical challenges associated with detaching from the extracellular matrix and metastasize. A key adaptive mechanism in this process is resistance to anoikis. In this review, we explore the molecular and biophysical mechanisms that enable cancer cells to resist anoikis, with a focus on mechanotransduction. We discuss the roles of integrin signaling, the YAP/TAZ pathway, the mechanosensitive ion channels, and actomyosin contractility in sustaining survival under mechanical stress conditions. Furthermore, we highlight the emerging contribution of soluble mediators, particularly the myokine irisin, which acts as mechanical mimetics by activating survival pathways typically triggered by matrix engagement. We also examined how mechanical heterogeneity across tumor types and metastatic routes shapes context-specific adaptation strategies. By bridging physical forces and cell survival signaling, this review underscores mechanostransduction as fundamental driver of metastatic competence and a promising target for therapeutic intervention.