Nuclear Mechanotransduction Across the Metastatic Cascade: Decoding Spatiotemporal Heterogeneity in Cancer Dissemination

ABSTRACT Cancer metastasis is the leading cause of cancer‐related mortality, involving complex interactions between tumor cells and the mechanically heterogeneous tumor microenvironment. The cell nucleus serves as a central mechanosensor in metastasis, dynamically perceiving and responding to the spatiotemporal evolution of mechanical signals throughout the metastatic cascade. These mechanical responses, such as nuclear deformation, nuclear envelope rupture and repair, and chromatin remodeling, not only directly regulate cellular behavior but also transduce biochemical signals through mechanotransduction pathways. While studies have focused on nuclear softening, membrane rupture/repair, and mechanical memory in metastasis, a comprehensive integration of the nucleus's spatiotemporal mechanical responses across the entire metastatic process is lacking. This review proposes a “nucleus‐centered cross‐stage mechanical signal decoding” framework, highlighting how nuclear mechanosensitive components dynamically decode mechanical signals in response to changes in metastatic stages and microenvironmental features. We further explore innovative anti‐metastasis strategies targeting key nuclear mechanosensitive elements and downstream transcriptional regulators, evaluating the therapeutic potential of physical interventions at specific metastatic stages. Additionally, we discuss ongoing controversies in the field, offering a novel perspective for understanding metastasis and developing integrated therapeutic paradigms.