Mechanical Memory in Cancer: From Force Sensing to Nuclear Encoding and Phenotypic Persistence

Abstract Cancer cells are shaped not only by mutations and soluble signals but also by the physical environments through which they pass. Matrix stiffening, compression, confinement, fluid shear and repeated deformation activate well-described mechanotransduction pathways. A more demanding question is whether their effects persist after the original stimulus disappears. Mechanical memory describes this persistence: a mechanically induced state that influences later behavior in a different physical setting. Evidence from selected breast, pancreatic, oral, bladder and brain tumor models suggest that prior mechanical exposure can leave lasting effects on contractility, migration, stem-like features and tumor formation, with emerging but less direct links to treatment response. However, the term is sometimes applied to any prolonged mechanoresponse, even when ongoing stimulation, slow signal decay or clonal selection has not been excluded. This review therefore organizes mechanical memory into four experimentally separable phases—acquisition, maintenance, recall and erasure—and ranks evidence according to cue withdrawal, functional persistence and control of alternative explanations. We examine how integrins, focal adhesions, mechanosensitive ion channels, Rho–ROCK signaling and the actomyosin cytoskeleton convey mechanical information to distributed storage layers that include the nucleus, transcriptional feedback, secreted factors and remodeled matrix. Particular attention is given to the metastatic cascade, in which mechanically induced states may persist, reset or be re-encoded as cells move between dissimilar tissues. Finally, we assess experimental models, possible effects on therapy response and whether mechanically encoded states can be prevented or erased.