Multi-omic profiling identifies TREM2+ lipid-laden macrophages as inflammatory drivers and therapeutic targets of colorectal cancer liver metastasis

Abstract

Tumor-associated macrophages (TAMs) are key regulators of the metastatic immune microenvironment, yet the specific TAM subsets that drive immune suppression and tumor progression in colorectal cancer liver metastasis (CRLM) remain poorly defined. Here, we integrated CyTOF, single-cell and spatial transcriptomics, bulk RNA sequencing, and lipidomics to identify a distinct population of lipid-laden, immunosuppressive TREM2⁺ TAMs enriched in CRLM. These cells exhibited high expression of lipid metabolism-related genes, including APOE, LIPA, and GPNMB, and accumulated abundant intracellular lipid droplets. Spatial analyses revealed their preferential localization at the invasive margins and within intratumoral colonic lumen-like structures-regions characterized by the buildup of APOE protein, mucinous material, and apoptotic tumor debris. Transcriptional analyses suggest these macrophages follow a Kupffer cell-related differentiation trajectory and acquire an immunoregulatory phenotype via uptake of tumor-derived lipids. Functionally, TREM2⁺ TAMs produced leukotrienes via the ALOX5/ALOX5AP pathway, which in turn sustained chronic inflammatory signaling. This inflammatory milieu potentiated neutrophil recruitment and fostered tumor cell stemness, thereby reinforcing an immunosuppressive metastatic niche and correlating with poor patient prognosis. In vivo murine depletion model and ex vivo organotypic tumor models confirmed that either selective ablation of TREM2⁺ TAMs or pharmacological inhibition of leukotriene synthesis alleviated immunosuppression and potentiated the efficacy of anti-PD-1 therapy. Our study defines a conserved lipid-associated TREM2⁺ TAM population as an essential contributor of immune evasion and microenvironment remodeling in liver metastasis, and suggest it as a potential therapeutic target in metastatic colorectal cancer.

Keywords: Colorectal cancer liver metastasis; Immune microenvironment; Leukotrienes; Lipid-laden macrophages; TREM2.