FABP7-mediated lipid-laden macrophages drive liver metastasis through metabolic reprogramming of tumor cells and CD8+ T cells

Abstract Abnormal metabolic process is involved in sequential steps of the pre-metastatic cascade and overt metastasis at the distant organ. However, the mechanisms underlying lipid metabolic reprogramming in macrophages regulates the formation of pre-metastic niche (PMN) during liver metastasis remain unknown. Here, we found that fatty acid binding protein 7 (FABP7) was up-regulated in the liver macrophages leading to lipid droplet accumulation in PMN of colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). This was partially mediated by hypoxia inducible factor-1 alpha (HIF-1α)-induced FABP7 expression that subsequently facilitated diacylglycerol acyltransferase 1 (DGAT1) activity in liver macrophages. FABP7-mediated lipid droplet induced protumoral M2-type macrophages in liver PMN, creating a highly immunosuppressive tumor microenvironment (TME). Knockout or pharmacologic inhibition of FABP7 reduced liver metastasis of CRC and PDAC, respectively. Mechanistically, lipid-laden macrophages induced by FABP7 transported their lipids to tumor cells and CD8+ T cells via exosomes, leading to heightened tumor cell proliferation and CD8 + T cell dysfunction through different metabolic reprogramming. Besides, FABP7 induced macrophages secreting pleiotrophin (PTN) to promote the proliferation of metastatic tumor cells by activating the PI3K-AKT signaling pathway. Collectively, our findings uncover a novel mechanism of FABP7-mediated lipid droplets in macrophage in liver PMN formation and metastasis, and suggest a prognostic and therapeutic potential of targeting FABP7 for liver metastasis.