Extracellular vesicle-mediated immunity-coagulation interaction in cancer-associated thrombosis during the immunotherapy era.

Cancer-associated thrombosis represents one of the major causes of mortality in patients with malignancies. In the era of immunotherapy, particularly with the widespread use of immune checkpoint inhibitors, thromboembolic events have emerged as an increasingly recognized complication. Extracellular vesicles (EVs), as small extracellular vesicles that facilitate intercellular communication, are now understood to play a pivotal role at the intersection of immune activation and coagulation. They transport diverse bioactive cargos, including tissue factor (TF), PD-L1, and proinflammatory noncoding RNAs, which together reprogram endothelial cells, platelets, and neutrophils toward a prothrombotic phenotype. During immune checkpoint inhibitor therapy, cytokine-driven EV release is amplified, increasing the systemic burden of procoagulant vesicles while simultaneously modulating the therapeutic efficacy of immune checkpoint blockade. This EV-mediated immune-coagulative interaction defines a proposed "inflammation-EV-coagulation axis," offering a mechanistic rationale for the rising incidence of cancer-associated thrombosis in immunotherapy-treated patients. Beyond their pathogenic role, EVs also present translational opportunities. Circulating TF⁺/PD-L1⁺ EVs link immune efficacy with thrombotic risk and can be dynamically monitored through advanced assays. Combined exosomal signatures improve prediction of immune checkpoint inhibitor response and toxicity, while targeting EV secretion offers a novel "antithrombotic without immune suppression" therapeutic strategy. Future directions include AI-driven models integrating exosomal, coagulation, and imaging data to enable early identification of high-risk patients and accurate cancer-associated thrombosis prediction. These advances highlight EVs' role in linking immunity and coagulation during immunotherapy, which can lead to new diagnostic and therapeutic strategies for mitigating cancer-associated thrombosis in the immunotherapy era.