Biomechanical networks of the pre-metastatic niche: Decoding biophysical determinants of tumor metastatic organotropism

In the metastatic cascade, biomechanics acts as an invisible engine that drives tumor malignancy. Shaping the intrinsic mechanical microenvironment of cancer cells facilitates their distant colonization and metastasis. Mechanical cues serve as physical fingerprints that orchestrate the formation of a pre-metastatic niche (PMN), which is a critical bottleneck in metastasis. However, biomechanically oriented antitumor strategies that integrate the physicochemical interactions of tumor metastasis remain underexplored in clinical therapy. In this review, we examine the role of biomechanics in shaping the PMN and propose a two-phase model of its evolution: mechanotransductive priming and mechanical niche reconstruction. Furthermore, we clarify the role of biomechanics in tumor organotropism and the impact of anatomical differences among organs on metastasis. In conclusion, a deeper understanding of the biomechanical dimensions of the PMN may inform the development of novel biomechanical interventions to prevent and control tumor metastasis. • Presentation of a novel two-phase model for PMN formation from a biomechanical perspective, encompassing Mechanotransductive Priming and Mechanical-Niche Reconstruction. • Emphasis on the underexplored yet significant role of biomechanics in PMN formation and tumor organotropism. • Integration of biomechanical and biochemical signaling networks, offering potential therapeutic targets to prevent metastatic spread. • Comprehensive and innovative perspective on tumor metastasis that underscores the mechanical dimensions of PMN, potentially guiding the development of novel anticancer strategies.