Mechano-regulation of cancer cell memory in tumor progression and therapy

Cancer cell memory, the ability to retain responses to prior environmental stimuli, has emerged as a key driver of tumor progression, therapeutic resistance, and immune evasion. Mechanical cues within the tumor microenvironment (TME), including matrix stiffness, viscoelasticity, and compressive stress, are increasingly recognized as critical regulators of such memory. These biophysical inputs not only influence immediate cellular behavior but also induce long-lasting transcriptional, epigenetic, and phenotypic changes that sustain cancer cell aggressive traits. In this review, we specifically highlight mechanobiology in shaping cancer cell memory. We summarize how extracellular matrix (ECM) composition and remodeling encodes mechanical inputs into stable gene expression programs that promote tumor progression, and highlight how mechano-regulated plasticity, membrane tension, chromatin remodeling, and epigenetic changes govern self-renewal, differentiation, and drug and immune resistance, underscoring how physical suppression contributes to chemo-, radio-, and targeted therapies failure. We further discuss emerging mechano-targeted strategies, including ECM-degrading agents, sonogenetic engineered cells, and stiffness-responsive nanoparticles, that seek to rewire cancer cell memory and improve treatment outcomes.