原发肿瘤细胞与远端器官的免疫细胞或基质细胞之间的信息传递是转移前微环境（PMN）形成的关键因素。了解这一机制对于制定针对肿瘤转移的有效治疗策略至关重要。我们的研究旨在证明富含 circ-0034880 的肿瘤源性细胞外囊泡 (TEV) 介导 PMN 和结直肠癌肝转移 (CRLM) 形成的假设，并且靶向富含 circ-0034880 的 TEVs 可能是一种有效的治疗策略PMN 形成和 CRLM。我们利用 qPCR 和 FISH 测量人 CRC 血浆、原发性 CRC 组织和肝转移组织中的 circRNA 表达水平。此外，我们采用免疫荧光、RNA测序和体内实验来评估富含circ-0034880的TEV对PMN形成和CRC转移的影响机制。应用 DARTS、CETSA 和计算对接模型探讨人参皂苷 Rb1 在阻止 PMN 形成中的药理作用。我们发现 circ-0034880 在 CRC 患者血浆外囊泡 (EV) 中高度富集，并与 CRLM 密切相关。从功能上讲，富含circ-0034880的TEV进入肝组织，并通过血流被肝脏中的巨噬细胞吸收。从机械角度来看，TEV 释放的 circ-0034880 增强了 SPP1highCD206 促肿瘤巨噬细胞的激活，重塑了支持转移的宿主基质微环境并促进了明显的转移。重要的是，我们的机制发现使我们发现天然产物人参皂苷 Rb1 通过减少 circ-0034880 生物发生来阻碍 SPP1highCD206 促肿瘤巨噬细胞的激活，从而抑制 PMN 形成并抑制 CRLM。富含 Circ-0034880 的 TEV 促进原发性巨噬细胞之间的强相互作用肿瘤细胞和 SPP1highCD206 促肿瘤巨噬细胞，促进 PMN 形成和 CRLM。这些发现表明，使用人参皂苷 Rb1 作为替代治疗剂来重塑 PMN 形成并预防 CRLM 的潜力。© 2024。作者。

Information transmission between primary tumor cells and immunocytes or stromal cells in distal organs is a critical factor in the formation of pre-metastatic niche (PMN). Understanding this mechanism is essential for developing effective therapeutic strategy against tumor metastasis. Our study aims to prove the hypothesis that circ-0034880-enriched tumor-derived extracellular vesicles (TEVs) mediate the formation of PMN and colorectal cancer liver metastasis (CRLM), and targeting circ-0034880-enriched TEVs might be an effective therapeutic strategy against PMN formation and CRLM.We utilized qPCR and FISH to measure circRNAs expression levels in human CRC plasma, primary CRC tissues, and liver metastatic tissues. Additionally, we employed immunofluorescence, RNA sequencing, and in vivo experiments to assess the effect mechanism of circ-0034880-enriched TEVs on PMN formation and CRC metastasis. DARTS, CETSA and computational docking modeling were applied to explore the pharmacological effects of Ginsenoside Rb1 in impeding PMN formation.We found that circ-0034880 was highly enriched in plasma extracellular vesicles (EVs) derived from CRC patients and closely associated with CRLM. Functionally, circ-0034880-enriched TEVs entered the liver tissues and were absorbed by macrophages in the liver through bloodstream. Mechanically, TEVs-released circ-0034880 enhanced the activation of SPP1highCD206+ pro-tumor macrophages, reshaping the metastasis-supportive host stromal microenvironment and promoting overt metastasis. Importantly, our mechanistic findings led us to discover that the natural product Ginsenoside Rb1 impeded the activation of SPP1highCD206+ pro-tumor macrophages by reducing circ-0034880 biogenesis, thereby suppressing PMN formation and inhibiting CRLM.Circ-0034880-enriched TEVs facilitate strong interaction between primary tumor cells and SPP1highCD206+ pro-tumor macrophages, promoting PMN formation and CRLM. These findings suggest the potential of using Ginsenoside Rb1 as an alternative therapeutic agent to reshape PMN formation and prevent CRLM.© 2024. The Author(s).