血栓形成是晚期癌症常见的并发症。然而，恶性肿瘤与血栓形成之间的细胞机制了解甚少。无折叠蛋白应激反应（UPR）是与晚期癌症有关的内质网应激反应。通过对胃癌和非小细胞肺癌患者进行前瞻性监测，对其血栓栓塞进行蛋白质组学评估，发现相比未形成血栓的患者，形成血栓的患者的血浆中UPR相关标记物的水平增加。UPR的诱导促进胃癌、肺癌和胰腺癌细胞上前凝血活性的释放，而IRE1α或PERK的拮抗剂则能阻断该释放。IRE1α/XBP1或PERK路径的siRNA介导的靶向沉默抑制了胰腺癌细胞释放含组织因子的细胞外囊泡（EVTF）的过程。UPR的诱导并未增加TF的合成，而是促进TF定位到细胞表面。通过Arf1的靶向沉默或GBF1的拮抗作用，证实了囊泡运输的作用，从而抑制了UPR诱导的TF传递到EVTF。我们的发现表明，UPR的激活导致囊泡运输增加，进而释放出具有促血栓作用的EVTF，从而提供了内质网应激和癌症相关血栓形成之间机制联系的证据。

Thrombosis is a common complication of advanced cancer. Yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasmas from gastric and non-small cell lung cancer patients who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasmas of patients who developed clots compared to those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors IRE1α or PERK. Release of extracellular vesicles bearing tissue factor (EVTF) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase TF synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by Arf1 knockdown or GBF1 antagonism, confirming the role of vesicular trafficking. Our findings show that UPR activation results in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.