Small extracellular vesicles in triple-negative breast cancer: from immune checkpoint modulation to clinical applications

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Among current treatment strategies, immune checkpoint inhibitor (ICI) therapy has shown promising clinical efficacy and is FDA-approved for TNBC. Immune checkpoints (ICPs) are regulatory proteins on immune cells that modulate immune responses to prevent overactivation and autoimmunity. Small extracellular vesicles (sEVs), a subtype of extracellular vesicles secreted by all cell types, mirror the molecular characteristics of their cells of origin. Tumor-derived sEVs can carry ICPs such as PD-L1, which interact with PD-1 on immune cells, mimicking the function of membrane-bound PD-L1 and contributing to immune evasion. sEVs derived from immune cells may carry ICPs like PD-1 and CTLA-4, potentially influencing immune responses and immunotherapy outcomes within the TNBC tumor microenvironment. Despite growing interest, the mechanisms by which ICP-bearing (ICP⁺) sEVs interact with immune and tumor cells in TNBC remain poorly understood. Existing reviews have explored ICPs and sEVs in cancer broadly, but few focus specifically on TNBC or the role of ICP⁺ sEVs in modulating its microenvironment. This review highlights the emerging role of ICP⁺ sEVs in TNBC progression, immune modulation, and immunotherapy resistance. We also examine their potential as biomarkers for disease monitoring and treatment response. Finally, we discuss future directions for ICP⁺ sEVs in clinical applications, including overcoming ICI therapy resistance in TNBC.