Multidimensional Regulatory Mechanisms of Extracellular Matrix Stiffness in Breast Cancer and Its Prospects for Clinical Translation.

Breast cancer (BC) metastasis is a leading cause of treatment failure and mortality. Most reviews emphasize canonical pathways such as epithelial-mesenchymal transition (EMT), adhesion signaling, and YAP/TAZ, whereas crosstalk between extracellular matrix (ECM) stiffness and other processes has not been systematically synthesized. This review highlights the temporal dynamics and spatial heterogeneity of ECM stiffness and examines its roles in metabolic reprogramming, immune regulation, epigenetic remodeling, exosome-mediated communication, and organ-specific premetastatic niche formation. ECM stiffening augments glycolytic and lipid metabolic programs and may align with metabolic preferences in TNBC and HER2+ subtypes, thereby facilitating drug resistance and metastatic progression. A stiff ECM can induce hypoxia and create a physical barrier that limits CD8+ T-cell infiltration and skews macrophage polarization; it can also activate immune checkpoint-associated programs via YAP/TAZ and TGF-β signaling, promoting immune evasion. Baseline tissue stiffness differs across metastatic organs, and dynamic remodeling may create windows for metastatic colonization, implying switches between soft and stiff states coupled with cellular reprogramming. In addition, stiffness can rewire migration-related networks through miRNAs, lncRNAs, DNA methylation, and histone modifications and can regulate exosome secretion and cargo to support ECM remodeling and subsequent BC cell seeding and colonization. Accordingly, we propose combination strategies targeting collagen cross-linking alongside mechanical and biochemical signaling and discuss translational challenges, including ECM heterogeneity, controlled drug delivery, and compensatory signaling networks. Future efforts integrating mechanobiology with multiomics and emerging imaging modalities may enable mechanical phenotyping and personalized intervention to suppress BC metastasis.