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Neutrophil extracellular trap formation (i.e., NETosis) is a crucial process in forming VTE in cancer patients. Nevertheless, how cancer cells contribute to NETosis remains unclear. This study investigated the potential activation effects of cancer cell\u2010derived extracellular vesicles (CC\u2010EVs) on neutrophils. Both small and large EVs (sEVs and lEVs) released from cancer cells are found to significantly induce NETosis in neutrophil\u2010like HL\u201060 (dHL\u201060)\u00a0cells. Following an in\u2010depth exploration of EV\u2010induced NETosis, the specific molecular pathways involved in this biological process are elucidated. CYBA enriched in CC\u2010lEVs is delivered to dHL\u201060, leading to a rapid increase in intracellular ROS levels and upregulation of citH3 expression. This cascade resulted in decondensed chromatin release and subsequent NETosis along with elevated MPO\u2010DNA levels. Injection of CC\u2010lEVs into mice caused more pronounced VTE, which is accompanied by increased peripheral blood levels of the MPO\u2010DNA and thrombin\u2010antithrombin complex. Inhibiting CYBA expression or ROS generation prevented NETosis in vitro and significantly reduced VTE in vivo. In conclusion, CC\u2010lEVs induce NETosis through the CYBA\u2010ROS\u2010citH3 pathway and increase VTE risk. Targeting CYBA expression or ROS production can provide novel strategies for preventing and treating VTE in high\u2010risk cancer patients.<\/jats:p>","DOI":"10.1002\/advs.202507867","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T10:44:45Z","timestamp":1753094685000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cancer Cell\u2010Derived Large Extracellular Vesicles Promote Venous Thromboembolism by Activating NETosis Through Delivering CYBA"],"prefix":"10.1002","volume":"12","author":[{"given":"Xiangji","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Beijing Friendship Hospital Capital Medical University State Key Laboratory of Digestive Health National Clinical Research Center for Digestive Diseases Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases  Beijing 100050 P. R. 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