Fig. 2

A schematic representation of the immune landscape of the TME in CRLM. GZM, granzyme; PRF, perforin; CTL, cytotoxic T lymphocyte; BA, bile acid; ex CD8⁺ T cell, exhausted CD8⁺ T cell; NET, neutrophil extracellular trap; CCRK, cell cycle-related kinase; sLewis-x, sialyl Lewis-x; CTLA-4, cytotoxic T lymphocyte antigen-4; SAA, serum amyloid A1 and A2; IGF-I, insulin-like growth factor-I. ① LSECs and NK cells produce IFNγ to upregulate functional Fas and induce apoptosis of cancer cells; PRF and GZM released from NK cells kill cancer cells. ② Disseminated CRC cells are phagocytosed by KCs along with the release of TNF-α, IL-1α and IL-1β. ③ APCs present neoantigens to CD8⁺ T cells, thus inducing the rapid proliferation of CD8⁺ T cells and their differentiation into CTLs. ④ CTLs secrete PRF and GZM, as assisted by IFNγ and TNF-α produced by Th1 cells to kill cancer cells. ⑤ LSECs are regulated by gut microbiota-modified bile acids to secret CXCL16, thus recruiting NKT cells to fight cancer cells. ⑥ M1 macrophages directly kill cancer cells by releasing cytotoxic ROS, NO and IL-12. ⑦ The function of cytotoxic CD8⁺ T cells is impeded due to the interplay between PD-L1 and PD-1. ⑧ The interaction between E-selectin and sialyl Lewis-x promotes the adhesion of CRC cells to LSECs. ⑨ Treg cells bind to APCs via the interaction between CTLA-4 and CD80/86 and produce TGF-β and IL-10 to suppress the activation of CTLs. ⑩ MDSCs, which are recruited by CXCL1 secreted from CRC cells, induce the activation of T_reg cells to impair the antigen-presenting activity of DC cells. ⑪ M2 macrophages produce IL-10, TGF-β and MMP to regulate matrix remodelling. ⑫ As induced by TGF-β secreted from KCs, HSCs are transformed to aHSCs and release TGF-β to promote ECM remodelling. ⑬ Lactic acid causes NK cell apoptosis by downregulating their intracellular pH. ⑭ TANs release CCL2 and CCL17 to recruit CCR2⁺ M2 macrophages and CCR4⁺ Treg cells. ⑮ As induced by IL-8, NETs trap CRC cells in the liver. ⑯ Hepatocyte-derived CCRK increases CXCL1 production to recruit PMN-MDSCs, thereby impairing NKT cell-mediated immunosurveillance. ⑰ As mediated by integrins and desmosomes, CRC cells adhere to hepatocytes, thus inducing the release of SAA and IGF-I from hepatocytes