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Lipid Metabolic Reprogramming in Tumor-Associated Macrophages

Metabolic reprogramming is critical for the polarization and function of tumor associated macrophages (TAMs) and carcinogenesis, whereas the underlying mechanism remains elusive. Here we show that monoacylglycerol lipase (MGLL) deficiency contributes to lipid accumulation in TAMs and tumor progression. MGLL regulates macrophage activation via CB2-TLR4 interaction. We also found that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)-associated macrophages, which correlates with the promoted tumorigenesis, as well as the enhanced accumulation and M2 polarization of TAMs. RIPK3 deficiency in TAMs reduces reactive oxygen species (ROS) and significantly inhibits and caspase1-mediated cleavage of peroxisome proliferator-activated receptors (PPARs) that enables PPAR activation and facilitates fatty acid metabolism including fatty acid oxidation (FAO), as well as induces M2 polarization in the tumor microenvironment. Our findings provide the molecular basis for lipid metabolic reprogramming of TAMs and highlight potential strategies for targeting cancer immunometabolism.

647 2020-08-20

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