Fig. 4

Schematic diagram depicting extracellular vesicles in the immune microenvironment of CRLM. Various cells in the hepatic immune microenvironment interact with CRC cells via extracellular vesicles to form a sophisticated immunosuppressive microenvironment that contributes to CRLM. The different pathways are indicated by different coloured arrows. ① CRC-derived hypoxia-induced exosomal miR-135a-5p is phagocytosed by KCs, thus blocking CD30-mediated CD4⁺ T-cell activation and promoting cell adhesion. ② Highly mCRC cells produce EV-packaged miR-181a-5p that activates HSCs. aHSCs release CCL20, which interacts with CCR6 expressed on CRC cells and activates CRC cells to promote the release of EV-packaged miR-181a-5p, thus contributing to reshaping the hepatic TME and forming a PMN; CRC-derived exosomal HSPC111 promotes the activation of HSCs, thus leading to the upregulation of CXCL5, which targets CRC-expressed CXCR2, increases the secretion of exosomal HSPC111 from CRC cells and promotes CRLM. ③ M2 macrophages release exosomal miR-21-5p and miR-155-5p, after which they shuttle into CRC cells, which contributes to the migration and invasion of CRC. ④ Exosomal miR-934 secreted from CRC cells induces M2 macrophage polarisation to promote CRLM. M2 macrophages release CXCL13, which interacts with CXCR5 in CRC cells and promotes the transcription of miR-934. ⑤ CRC cells secrete exosomal miR-25-3p to stimulate endothelial cells, thus leading to vascular leakage and vasculogenesis