FABP7-mediated lipid-laden macrophages drive the formation of pre-metastatic niche and liver metastasis.

Abstract

Abnormal metabolism processes play a crucial role in the establishment of the pre-metastatic niche (PMN) and the subsequent metastasis to distant organs. However, the precise mechanisms underlying the lipid metabolic reprogramming of macrophages within the liver PMN remain elusive. In this study, we observed an upregulation of fatty acid-binding protein 7 (FABP7) in liver macrophages, which resulted in the accumulation of lipid droplets (LDs) within the PMN of colorectal cancer and pancreatic ductal adenocarcinoma. This accumulation was found to be mediated by the HIF-1α-induced expression of FABP7, which in turn enhanced DGAT1 activity in these macrophages. Furthermore, FABP7-induced lipid-laden macrophages were observed to deliver lipids to CD8⁺ T and tumor cells via exosomes. This process led to CD8⁺ T cell dysfunction and increased tumor cell proliferation through metabolic reprogramming. Importantly, genetic knockout or pharmacological inhibition of FABP7 reduced liver metastasis. Our findings reveal a novel mechanism involving FABP7-mediated LD in macrophages that contributes to liver PMN formation and metastasis. This suggests that targeting FABP7 may offer prognostic and therapeutic potential in addressing liver metastasis.