Exosomal MicroRNAs as Drivers of Desmoplasia and Treatment Resistance in Breast Cancer: Mechanisms, Biomarker Potential, and Therapeutic Opportunities.

Exosomal microRNAs (miRNAs) are key mediators of intercellular communication in the breast cancer tumor microenvironment (TME), facilitating bidirectional signaling between malignant cells and the desmoplastic stroma. This review explores current evidence on their dual roles as drivers of stromal remodeling and as circulating biomarkers of therapeutic resistance across major breast cancer subtypes, including triple-negative breast cancer (TNBC), hormone receptor-positive (ER+/PR+) disease, and HER2-amplified tumors. We outline how miR-9, miR-21, and miR-181 family members promote cancer-associated fibroblast (CAF) activation, increase extracellular matrix (ECM) stiffness, and sustain a reverse Warburg phenotype. We then detail subtype-specific resistance mechanisms: miR-181 family members suppress BCLAF1 to block doxorubicin-induced apoptosis; miR-221/222 downregulates ESR1 and p27Kip1 to confer tamoxifen resistance; miR-155 impairs homologous recombination in TNBC; and miR-1246 sustains PI3K/AKT signaling in HER2-positive disease. We also evaluate circulating exosomal miRNA panels as liquid biopsy tools for predicting chemotherapy response and tracking resistance emergence. Finally, we discuss therapeutic strategies including antagomirs, miRNA replacement therapy and engineered exosome platforms, and address key challenges such as assay standardization and regulatory hurdles, that must be overcome for clinical translation.