A Critical Reassessment of Tumor Metastasis Simulation in Murine Models: Insights Into Methodological Advances and Biological Relevance

Abstract Metastasis drives treatment failure and cancer mortality, yet preclinical studies still rely heavily on subcutaneous xenograft models that prioritize tumor growth over metastatic biology. This disconnection from clinical reality significantly contributes to the high failure rate of experimental therapies in trials. Here, current mechanistic insights is integrated into metastasis and critically assess transplantation models to inform rational model selection for metastasis research. Tumor transplantation models exhibit distinct dissemination patterns governed by implantation methodology rather than intrinsic tumor properties. Subcutaneous models, while technically accessible, predominantly assess primary tumor growth and fail to capture critical metastatic steps like intravasation, pre‐metastatic niche formation, and organotropism. Orthotopic transplantation faithfully replicates native tissue microenvironments, enabling simultaneous assessment of tumor growth and metastatic potential. Intravascular models, while inducing rapid colonization, distort natural metastatic progression by skipping early dissemination stages. Metastatic site transplantation isolates microenvironmental impacts on tumor adaptation but fails to capture de novo metastatic initiation. Ultimately, three strategies is proposed for preventing metastasis: Eradicating circulating tumor cells, blocking colonization, and stifling outgrowth. This perspective catalyzes the strategic advancement of tumor metastasis models, thereby strengthening the reliability of preclinical findings and accelerating their clinical translation.