Numerous studies have proved that cell‐nonautonomous regulation of neoplastic cells is a distinctive and essential characteristic of tumorigenesis. Two way communications between the tumor and the stroma, or within the tumor significantly influence disease progression and modify treatment responses. In the tumor microenvironment (TME), malignant cells utilize paracrine signaling initiated by adjacent stromal cells to acquire resistance against multiple types of anticancer therapies, wherein extracellular vesicles (EVs) substantially promote such events. EVs are nanoscaled particles enclosed by phospholipid bilayers, and can mediate intercellular communications between cancerous cells and the adjacent microenvironment to accelerate pathological proceeding. Here we review the most recent studies of EV biology and focus on key cell lineages of the TME and their EV cargoes that are biologically active and responsible for cancer resistance, including proteins, RNAs, and other potentially essential components. Since EVs are emerging as novel but critical elements in establishing and maintaining hallmarks of human cancer, timely and insightful understanding of their molecular properties and functional mechanisms would pave the road for clinical diagnosis, prognosis, and effective targeting in the global landscape of precision medicine. Further, we address the potential of EVs as promising biomarkers in cancer clinics and summarize the technical improvements in EV preparation, analysis, and imaging. We highlight the practical issues that should be exercised with caution to guide the development of targeting agents and therapeutic methodologies to minimize cancer resistance driven by EVs, thereby allowing to effectively control the early steps of disease exacerbation.

中文翻译：

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肿瘤微环境中的细胞外囊泡：治疗耐药性、临床生物标志物和靶向策略

大量研究证明，肿瘤细胞的细胞非自主调节是肿瘤发生的一个独特而重要的特征。肿瘤和基质之间或肿瘤内的双向通信显着影响疾病进展并改变治疗反应。在肿瘤微环境 (TME) 中，恶性细胞利用由相邻基质细胞启动的旁分泌信号传导来获得对多种抗癌疗法的抵抗力，其中细胞外囊泡 (EV) 大大促进了此类事件。EVs是由磷脂双层包裹的纳米级颗粒，可以介导癌细胞与相邻微环境之间的细胞间通讯，从而加速病理进程。在这里，我们回顾了 EV 生物学的最新研究，并重点关注 TME 的关键细胞谱系及其具有生物活性并负责抗癌的 EV 货物，包括蛋白质、RNA 和其他潜在的必需成分。由于 EV 正在成为建立和维持人类癌症标志的新颖但关键的元素，因此及时和深入地了解其分子特性和功能机制将为临床诊断、预后和全球精准医学领域的有效靶向铺平道路。此外，我们探讨了 EV 作为癌症临床有前景的生物标志物的潜力，并总结了 EV 制备、分析和成像方面的技术改进。