RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis

• Published in: Cancer immunology research Vol. 8; no. 5; p. 710
• Main Authors: Wu, Lei, Zhang, Xiao, Zheng, Lu, Zhao, Huakan, Yan, Guifang, Zhang, Qi, Zhou, Yu, Lei, Juan, Zhang, Jiangang, Wang, Jingchun, Xin, Rong, Jiang, Lu, Peng, Jin, Chen, Qian, Lam, Sin Man, Shui, Guanghou, Miao, Hongming, Li, Yongsheng
• Format: Journal Article
• Language: English
• Published: United States 01.05.2020
• Subjects: Animals; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Fatty Acids - metabolism; Humans; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; PPAR gamma - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - immunology; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Tumor Microenvironment - immunology
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-19-0261

Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)-associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.