理由：越来越多的证据表明肿瘤微环境在产生耐药性中发挥着作用。这种微环境的一个关键要素是细胞间通讯，其中包括释放含有各种物质的膜封装囊泡，即细胞外囊泡 (EV)。了解 EV 如何导致获得性耐药具有重要的临床意义。方法：使用基于差速离心的方法从已建立的细胞系和人血浆中分离EV。 EV 的 TMT 标记蛋白质组学分析揭示了丰富的代谢转运蛋白。使用 Kaplan-Meier 生存图评估了对酪氨酸激酶抑制剂产生耐药性的患者血浆和细胞系 EV 中 SLC1A5 表达的增加及其与无进展生存的关系。 SLC1A5 的基因敲低和过表达用于验证其对酪氨酸激酶抑制剂 (TKI) 耐药性的影响。使用插入物的共培养测定用于评估耐药 EV 对正常成纤维细胞和上皮细胞的影响。接下来，在体外培养小鼠源性肿瘤切片（MDTS）以评估耐药 EV 的效果。结果：我们在此报告，TKI 敏感细胞在与源自 TKI 抗性细胞系的 EV 一起孵育后会产生抗性。代谢转运蛋白，特别是 SLC1A5 和 SLC25A5，在源自 TKI 耐药细胞的 EV 和来自 TKI 耐药肿瘤患者的血浆以及 TKI 耐药细胞系中上调。此外，我们还提供了 EV 诱导抗性后 pSTAT3 和干性标记 ALDH1A1 丰度增加的证据。值得注意的是，耐药的 EV 触发肺源性成纤维细胞向肿瘤相关成纤维细胞的表型和功能转换，显着增加其迁移和侵袭能力。结论：我们的研究结果支持肿瘤源性 EV 中代谢转运蛋白在重塑肿瘤微环境以促进治疗耐药性方面的作用，这可能具有潜在的诊断、预后和治疗意义。© 作者。

Rationale: Growing evidence points to the tumor microenvironment's role in developing drug resistance. A key element of this microenvironment is inter-cellular communication, which includes the release of membrane-encapsulated vesicles containing various cargo, known as extracellular vesicles (EVs). Understanding how EVs contribute to acquired resistance holds significant clinical implications. Methods: Differential centrifugation-based methods were used to isolate EVs from established cell lines and human plasma. TMT labeling proteomics analysis of EVs revealed an abundance of metabolic transporter proteins. Increased expression of SLC1A5 in EVs of patient-derived plasma and cell lines rendered resistant to tyrosine kinase inhibitors and its relationship with progression-free survival was assessed using Kaplan-Meier survival plot. Gene knockdown and overexpression of SLC1A5 were used to validate its effect on Tyrosine kinase inhibitor (TKI) resistance. Co-culture assays using inserts was used to evaluate the effect of resistant EVs on normal fibroblasts and epithelial cells. Next, mouse-derived tumor slices (MDTS) were cultured in vitro to assess the effect of resistant EVs. Results: We report here that TKI-sensitive cells are rendered resistant upon incubation with EVs derived from TKI-resistant cell lines. Metabolic transporters, in particular SLC1A5 and SLC25A5, are upregulated in EVs derived from TKI-resistant cells and plasma from patients harbouring TKI-resistant tumors and in TKI-resistant cell lines. Furthermore, we also provide evidence for the increased abundance of pSTAT3 and the stemness marker ALDH1A1 upon EV-induced resistance. Notably, resistant EVs trigger phenotypic and functional switching of lung-derived fibroblasts into tumor-associated fibroblasts, significantly increasing their migratory and invasive capacities. Conclusions: Our findings support the role of metabolic transporters within tumor-derived EVs in reshaping the tumor microenvironment to promote therapy resistance, which could have potential diagnostic, prognostic, and therapeutic implications.© The author(s).