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Abstract
Breast cancer progression and metastatic dissemination are not solely determined by intrinsic tumor cell properties but are profoundly influenced by the surrounding tumor microenvironment (TME). The TME comprises a dynamic network of stromal cells, immune infiltrates, endothelial cells, extracellular matrix (ECM), soluble mediators, and metabolic gradients that collectively regulate tumor growth, invasion, angiogenesis, immune evasion, and therapeutic resistance. Reciprocal interactions between malignant epithelial cells and stromal components activate multiple signalling pathways, including TGF-β, PI3K/Akt, NF-κB, Wnt/β-catenin, and hypoxia-inducible factor signalling, which orchestrate epithelial–mesenchymal transition, extracellular matrix remodelling, and metastatic niche formation. Cancer-associated fibroblasts remodel the ECM and secrete pro-tumorigenic cytokines, while tumor-associated macrophages and regulatory T cells suppress anti-tumor immunity and facilitate angiogenesis. Hypoxia and acidic metabolism further enhance genomic instability and drug resistance. Emerging evidence highlights the plasticity of the TME and its role in shaping therapeutic responses, emphasizing the importance of targeting stromal and immune components alongside tumor cells. Advances in single-cell sequencing, spatial transcriptomic, and organoid co-culture models have refined our understanding of cellular heterogeneity and intercellular crosstalk within breast tumors. This review synthesizes mechanistic insights into the cellular, molecular, and biophysical determinants of the breast cancer TME, emphasizing their contribution to invasion and metastasis. Understanding these complex interactions offers opportunities for developing precision therapeutics that modulate the microenvironment to enhance treatment efficacy and overcome resistance.