Immunomodulatory roles of tumor-derived extracellular vesicles and their therapeutic implications in breast cancer

Breast cancer remains the most prevalent malignancy and a major therapeutic challenge in women worldwide, with the tumor immune microenvironment (TIME) playing a pivotal role in disease progression and treatment resistance. Tumor-derived extracellular vesicles (TEVs) serve as critical mediators of intercellular communication within TIME by transporting bioactive molecules such as proteins, nucleic acids, and lipids, thereby modulating both innate and adaptive immune responses to promote immunosuppression and immune evasion. TEVs deliver immunosuppressive factors, including programmed death-ligand 1 (PD-L1), transforming growth factor-beta (TGF-β), and specific miRNAs, which impair dendritic cell maturation, drive macrophage polarization toward an M2-like phenotype, suppress nature killer (NK) cell cytotoxicity, and induce T-cell exhaustion or regulatory T-cell expansion. Beyond their immunosuppressive roles, TEVs hold significant diagnostic and prognostic potential, functioning as non-invasive biomarkers (e.g., human epidermal growth factor receptor 2 (HER2), epithelial cell adhesion molecule (EpCAM), and miR-21 detection) and predictors of immunotherapy response. Therapeutic strategies targeting TEV biogenesis, release, or cargo may enhance immunotherapy efficacy, while engineered TEVs loaded with tumor antigens or immunostimulatory molecules, offer novel immunotherapeutic opportunities. However, challenges such as TEV heterogeneity, standardization in isolation techniques, in vivo targeting efficiency, and safety concerns hinder clinical translation. Future research should integrate multidisciplinary approaches to optimize TEV-based applications, advancing their potential as diagnostic tools and personalized immunomodulatory therapies in breast cancer.