Mechanistic Interplay Between Biomechanical Signaling and Epigenetic Regulation: Targeted Therapy Against Tumor Development and Malignant Progression.

An aberrant mechanical microenvironment is a major driver of malignant tumor progression. Its effects are not limited to the immediate regulation of tumor cell behavior. Through mechanotransduction-mediated epigenetic remodeling, external physical cues can also be converted into persistent malignant programs. Mechanical alterations in the physical tumor microenvironment, including increased matrix stiffness, compressive stress, fluid shear stress, and spatial confinement, can be sensed by integrin adhesion complexes, mechanosensitive ion channels, and the nucleo-cytoskeletal system. These signals are then transmitted to the nucleus through multiple pathways, leading to systematic remodeling of multilayered epigenetic networks, including DNA methylation, histone modifications, chromatin accessibility, and RNA modifications. Notably, some mechanically induced nuclear alterations can be retained even after the original stimulus is attenuated, thereby forming "mechanical memory." This enables tumor cells to maintain malignant phenotypes such as invasion, metastasis, stem-like states, and therapeutic resistance during transitions between distinct microenvironments. In this review, we systematically summarize the key mechanisms by which mechanical signals regulate epigenetic processes across multiple epigenetic layers, with a particular focus on the basis and functional significance of mechanical memory. We also discuss therapeutic strategies targeting mechano-epigenetic coupling nodes and highlight recent advances in clinical translation. A deeper understanding of how mechanical cues are epigenetically written into and maintained as stable malignant states will provide new theoretical insights and potential therapeutic targets for the precision treatment of solid tumors.