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The metastatic diversity of cancers is driven by heterogeneity in physicochemical properties, cellular composition, and signaling networks among primary tumors, dissemination routes, and target organs. Currently, the stage\u2010dependent and route\u2010dependent molecular mechanisms underlying metastasis and potential pan\u2010cancer therapeutic targets remain incompletely defined. Here, we systematically discuss the genomic, chromosomal, and epigenetic evolution of metastatic tumor cells (MTCs) following their spatiotemporal trajectory from in situ evolution to metastatic colonization. We describe their migration behaviors and interaction patterns within the migratory tumor microenvironment across hematogenous, lymphatic, and perineural routes, and the establishment and remodeling of organ\u2010specific metastatic niches. We also review the progress and limitations of metastasis\u2010oriented diagnostic stratification and therapeutic interventions. We argue for the shift of antimetastatic strategies from target\u2010centric approaches to precise interventions that match timing, routes, biomarkers, and endpoints. By integrating the molecular mechanisms underlying spatiotemporal changes during cancer metastasis, this review delineates the spatiotemporal evolutionary landscape of metastasis and the MTC\u2013microenvironment interaction patterns, thereby offering insights for future clinical translation of metastasis\u2011targeted therapies.<\/jats:p>","DOI":"10.1002\/mco2.71026","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:08:31Z","timestamp":1790924911000},"source":"Crossref","is-referenced-by-count":0,"title":["Cancer Cell Metastasis: From Molecular Mechanisms to Therapeutic Strategies"],"prefix":"10.1002","volume":"7","author":[{"given":"Yupeng","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of General Surgery Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"},{"name":"Key Laboratory of Research in Pancreatic Tumor Chinese Academy of Medical Sciences  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