Most patients with cholangiocarcinoma (CCA) develop extrahepatic malignant biliary obstructions, which require palliative drainage to normalize bilirubin levels and to improve the patients’ overall survival. Here, we report that the infusion of methotrexate-containing plasma-membrane microvesicles derived from apoptotic human tumour cells into the bile-duct lumen of patients with extrahepatic CCA mobilized and activated neutrophils and relieved biliary obstruction in 25% of the patients. Neutrophil recruitment by the microvesicles was associated with an increase in uridine diphosphate glucose and complement C5, and led to the degradation of the stromal barrier of CCA. The microvesicles induced pyroptosis of CCA cells through a gasdermin E-dependent pathway, and their intracellular contents released upon CCA-cell death activated patient-derived macrophages into producing proinflammatory cytokines, which attracted a secondary wave of neutrophils to the tumour site. Our findings suggest a possible treatment for the alleviation of obstructive extrahepatic CCA with few adverse effects, and highlight the potential of tumour-cell-derived microvesicles as drug carriers for antitumour therapies.

大多数胆管癌患者会发展为肝外恶性胆道梗阻，需要姑息性引流以使胆红素水平正常化并改善患者的整体生存率。在这里，我们报告说，将来自凋亡性人类肿瘤细胞的含甲氨蝶呤的血浆膜微囊泡注入肝外CCA所动员并激活的嗜中性粒细胞患者的胆管腔中，在25％的患者中缓解了胆道梗阻。微泡募集的中性粒细胞与尿苷二磷酸葡萄糖和补体C5的增加有关，并导致CCA基质屏障的降解。微囊泡通过gasdermin E依赖性途径诱导CCA细胞的热凋亡，CCA细胞死亡后释放的细胞内内容物激活了患者来源的巨噬细胞，使其产生促炎性细胞因子，从而将嗜中性粒细胞的第二波吸引到肿瘤部位。我们的研究结果表明，一种缓解阻塞性肝外CCA的可能的疗法几乎没有副作用，并且强调了肿瘤细胞衍生的微泡作为抗肿瘤治疗药物载体的潜力。