Targeting myeloid cells with platelet-derived extracellular vesicles to overcome resistance of immune checkpoint blockade therapy

Immune checkpoint blockade (ICB) therapy is designed to boost antitumor immune responses, yet it may unintentionally alter the chemokine profile, which can attract suppressive myeloid cells to the tumor, leading to acquired immune resistance. To address this, we developed a platform that targets myeloid cells post-ICB therapy using platelet-derived extracellular vesicles (PEVs). Unlike free drug administration, this system selectively targets anti-PD-L1-treated tumors through the CXCL-CXCR2 axis, effectively redirecting myeloid cells and overcoming ICB resistance. Consequently, mice exhibited robust responses to subsequent ICB therapy cycles, resulting in significantly enhanced tumor clearance and prolonged survival. The PEVs’ targeting capability was also effective in tumors treated with chemotherapy and radiotherapy, suggesting a wide range of potential applications. In summary, PEVs offer a versatile platform for targeted immunomodulation to counteract acquired immune resistance during ICB therapy.