Masterclass by Giorgio Scita: Is Mechanobiology a new emerging tumour hallmark?

Cancer has long been defined by its genetic alterations, yet this view is increasingly insufficient. Tumors are not merely collections of mutated cells but dynamic physical systems in which mechanical forces actively shape disease evolution. Emerging evidence positions mechanobiology as a critical, and possibly missing, hallmark of cancer. This lecture challenges the gene-centric paradigm by highlighting how tissue architecture, extracellular matrix organization, and physical constraints regulate tumor behavior. In particular, we discuss the concept of epithelial tissues poised at the edge of a jamming–unjamming transition, where subtle changes in mechanical state can trigger a switch from solid-like quiescence to fluid-like collective invasion. We present evidence that endocytic rewiring, exemplified by RAB5A, drives tissue fluidification and couples mechanical remodeling to innate immune signaling via the cGAS/STING–interferon axis. These findings suggest that tumor progression is not only genetically encoded but mechanically enabled. By integrating physics with cancer biology, mechanobiology emerges not simply as a contributing factor, but as a fundamental organizing principle of malignancy, with profound implications for diagnosis, prognosis, and therapeutic intervention.