Orchestrating organotropism: miRNA‑driven mechanisms of site‑specific metastasis in triple‑negative breast cancer (Review)

Triple-negative breast cancer (TNBC), characterized by its aggressive nature and poor prognosis, exhibits a pronounced propensity for organ-specific metastasis, which remains the primary cause of treatment failure and mortality. The present review synthesizes current knowledge on the pivotal role of microRNAs (miRNAs/miRs), particularly those shuttled via tumor-derived exosomes, in orchestrating the complex molecular mechanisms underlying TNBC metastasis to the brain, bone, liver and lungs. In addition, the review highlights how specific miRNAs function as master regulators of organotropic metastasis by facilitating pre-metastatic niche (PMN) formation through miRNA-target gene-microenvironment remodeling cascades. Key mechanisms discussed include: Brain metastasis, in which miR-105 disrupts the blood-brain barrier by targeting zonula occludens protein 1 and miR-19a activates astrocytic STAT3 signaling to promote tumor extravasation and survival; bone metastasis, in which miR-218-5p disrupts the osteoprotegerin/receptor activator of nuclear factor κB ligand balance and miR-21 drives a self-perpetuating osteolysis-growth factor-tumor proliferation loop via programmed cell death 4/nuclear factor of activated T cells 1 and TGF-β feedback; liver metastasis, in which miR-122 reprograms the host metabolism by suppressing pyruvate kinase M2 and O-GlcNAc transferase, and contributes to immune evasion; and lung metastasis, in which miR-200 family members regulate endothelial permeability and epithelial-mesenchymal transition. Common metastasis drivers, including miR-10b, miR-21, the miR-200 family and the miR-221/222 cluster, exhibit both shared and organ-specific functions. Although targeting these miRNA networks holds therapeutic promise, notable challenges persist, including organ-specific delivery efficiency, particularly across the blood-brain barrier, potential toxicity, including miR-10b hepatotoxicity, and scalable exosome engineering for drug delivery. Emerging strategies offering potential solutions include engineered exosomes and localized implantable systems. Understanding the spatiotemporal dynamics of miRNA-mediated organotropism, facilitated by advanced technologies, will be crucial for the future development of precision therapies to combat TNBC metastasis.