An updated review on the role of extracellular vesicles in immune system modulation in breast cancer with special emphasis on immune checkpoint regulators.

Breast cancer progression and resistance to therapy are strongly influenced by immune evasion within the tumor microenvironment. Immune checkpoint signaling is a major mechanism by which cancer cells evade immune surveillance, thereby promoting tumor progression and reducing the effectiveness of immunotherapy. Recent evidence suggests that extracellular vesicles (EVs) are important mediators of communication between tumor, stromal, and immune cells, enabling the transfer of proteins, nucleic acids, lipids, and other bioactive molecules that regulate immune responses. This review discusses current knowledge on the role of EVs in immune checkpoint regulation in breast cancer, with an emphasis on both programmed death-ligand 1 (PD-L1)-dependent and additional immunosuppressive pathways that collectively contribute to immune escape. A literature review was conducted using PubMed, Google Scholar, and Web of Science, focusing on studies from the past decade related to EV biology, immune checkpoints, and breast cancer. Findings from multiple studies indicate that tumor-derived EVs contribute to immunosuppression by impairing T-cell function, promoting immune tolerance, facilitating metastatic progression, and supporting resistance to immunotherapy. Importantly, EV-mediated effects are different for the breast cancer subtypes, which may play a role in treatment response, disease progression, and clinical outcomes. EVs also show potential as minimally invasive biomarkers for disease monitoring and as therapeutic targets or delivery systems for precision medicine. Overall, this review highlights current evidence on EV-mediated immune checkpoint regulation in breast cancer, highlighting PD-L1 and CTLA-4associated mechanisms as key drivers of immune evasion and promising targets for precision immunotherapy.