Metastatic immune microenvironment remodeling by malignant epithelial cells drives colorectal cancer hepatic...

Advanced CRC patients frequently accompanied by hepatic metastasis (HM). Malignant epithelial cells, as the core in metastasis, have not been fully investigated. This study investigates the role of malignant epithelial cells in CRC HM and its underlying mechanisms.

Multi-omics were utilized to perform comprehensive analysis of CRC HM. "Scissor" was employed to identify malignant epithelial cell (Scissor⁺ epithelial cell). Furthermore, "MIME" was utilized to establish a HM-associated prognostic signature for calculating Scissor-related risk score (SRRS). Then, "CellChat" and "NicheNet" were utilized to identify significant crosstalk between Scissor⁺ epithelial cells and various immunosuppressive cells. Finally, RT-qPCR, Western blotting and Transwell migration assays were utilized for validation.

The heterogeneity landscape of malignant epithelial cells in CRC HM has been delineated. Notably, EMT-related pathways were enriched in Scissor⁺ epithelial cells. Then, three genes (HSPB1, HEBP2 and ZFP36L1) were identified by "MIME" to calculate SRRS. Higher SRRS scores indicate worse patient prognosis. Intriguingly, Scissor⁺ epithelial cells recruit CD4⁺ Treg (Regulatory T cells) and CD8⁺ Tex (Exhausted T cells) via MIF and MK pathways, while simultaneously attracting normal macrophages and convert them to SELENOP⁺ tumor-associated macrophages (TAMs) through LGALS9-HAVCR2 axis. Moreover, the comparison of hepatic immune microenvironment before and after HM further substantiates the critical roles of CD4⁺ Treg and SELENOP⁺TAMs in HM.

Scissor⁺ epithelial cells reshape the metastatic immune microenvironment to promote CRC HM by recruiting CD4⁺ Treg and SELENOP⁺ TAMs. Furthermore, higher SRRS score can be used to predict unfavorable clinical outcomes in CRC patients with HM.