积累的证据揭示癌细胞与M2巨噬细胞之间的相互作用在肝细胞癌的肿瘤发生中起着重要作用。然而，肿瘤衍生的外泌体、巨噬细胞的M2极化和肝转移之间的机制仍不清楚。因此，有必要探究它们对HCC的肿瘤微环境的影响。利用透射电子显微镜、纳米颗粒测试和特殊生物标记物分析来表征外泌体，利用高通量测序技术评估microRNA的差异表达。利用体外和体内实验确定了miR-200b-3p外泌体的功能。使用RNA pull-down和荧光素酶基因报告实验来测量microRNA与ZEB1以及癌细胞和巨噬细胞之间的相互作用。 通过计算机模拟分析，我们确定在HCC患者中miR-200b-3p外泌体表达水平较高，特别是在复发性HCC患者中。我们证明，HCC细胞来源的miR-200b-3p外泌体被M0巨噬细胞内化，并通过下调ZEB1和上调白细胞介素-4诱导M2极化。因此，在M2巨噬细胞中激活了JAK/STAT信号通路，导致PIM1和VEGFα表达增加。这些细胞因子加速了HCC的增殖和转移，从而导致HCC细胞与M2巨噬细胞之间的正反馈循环。研究表明，HCC细胞来源的miR-200b-3p外泌体通过调节细胞因子分泌和JAK/STAT信号通路，促进巨噬细胞的增殖和极化，导致HCC的转移。这些发现展示了肿瘤微环境中癌细胞与免疫细胞之间存在一种新型正反馈环路，为癌症研究提供了新思路。 2023年亚太肝病研究协会。

Accumulating evidence has elucidated that the interaction between cancer cells and M2 macrophages plays an important role in the tumorigenesis of hepatocellular carcinoma (HCC). However, the mechanism connecting tumor-derived exosomes, M2 polarization of macrophages, and liver metastasis remain unclear. Therefore, it is necessary to explore their influence on the tumor microenvironment of HCC.Transmission electron microscopy, nanometer particle testing, and special biomarker analysis were utilized to characterize exosomes, while the differential expression of microRNAs was evaluated using high-throughput sequencing technology. The functions of miR-200b-3p exosomes were confirmed using in vitro and in vivo assays. The interactions between microRNAs and ZEB1 as well as cancer cells and macrophages were measured using RNA pull-down and luciferase gene reporter assays.Using in silico analysis, we identified high levels of miR-200b-3p exosome expression in patients with HCC, particularly with relapsed HCC. We demonstrated that HCC cell-derived miR-200b-3p exosomes were internalized by M0 macrophages and induced M2 polarization by downregulating ZEB1 and upregulating interleukin-4. As a result, the JAK/STAT signaling pathway was activated in M2 macrophages, leading to increased PIM1 and VEGFα expression. These cell factors accelerated the proliferation and metastasis of HCC, resulting in a feedback loop between HCC cells and M2 macrophages.The study illustrates that HCC cell-derived miR-200b-3p exosomes facilitate the proliferation and polarization of macrophages by modulating cytokine secretion and the JAK/STAT signaling pathway, leading to the metastasis of HCC. These findings demonstrate the existence of a novel feedback loop between cancer cells and immune cells in the tumor microenvironment, presenting a new concept in cancer research.© 2023. Asian Pacific Association for the Study of the Liver.