APOC1⁺IFI30⁺ TAMs orchestrate colorectal cancer liver metastasis by coupling cholesterol biosynthesis with secretion of immunosuppressive factors.

Tumor-associated macrophages (TAMs) play a crucial role in colorectal cancer (CRC) metastasis, particularly in the establishment of the liver metastatic niche. TAMs facilitate metastasis by enabling epithelial-mesenchymal transition (EMT) and suppressing anti-tumor immunity. While their roles in primary tumors have been extensively investigated, their functions at metastatic sites remain poorly understood. In this study, we analyzed the single-cell RNA sequencing data from 46 CRC patients, encompassing 402,972 cells, to identify macrophage subsets associated with liver metastasis. A distinct population of APOC1+ IFI30+ TAMs was identified and found to be significantly enriched in metastatic liver lesions. Compared to primary tumors (PT), the number of APOC1+ IFI30+ TAMs significantly increased at liver metastatic sites after CRC cells metastasized to the liver. We employed spatial transcriptomics to validate the above conclusions. These TAMs exhibited significantly enhanced immunosuppressive capacity and cholesterol synthesis metabolism. Further investigation showed that TAMs within metastatic niches reprogram the mevalonate pathway to enhance cholesterol synthesis, characterized by upregulation of key genes such as HMGCR and ACAT1/2. These TAMs act on surrounding tumor cells by secreting cholesterol and cytokines such as TNFSF12, TGFB1, MIF and LGALS9, thereby enhancing tumor adhesion and proliferation and creating an immunosuppressive microenvironment to continuously support tumor growth. Our findings provided new insights into the complex interactions among TAMs, immune cells, and tumor cells within CRC metastatic microenvironment, highlighting potential therapeutic targets to disrupt TAMs-mediated immune evasion and metastatic progression.