Single cell analysis of the tumor microenvironment in OXCT1-deficient-macrophages hepatocellular carcinoma mice (PRJCA018005)
The liver is the major organ of ketogenesis while ketones are mainly metabolized in periphery tissues through the critical enzyme OXCT1. We previously found that hepatocellular carcinoma (HCC) cells reactivate ketolysis through OXCT1 expression to promote tumor progression. Here, we found that inhibiting aberrant OXCT1 expression in tumor-associated macrophages (TAMs) enhances antitumor immunity through the succinate-mediated H3K4me3-Arg1 pathway. Specifically, we found that OXCT1 was highly expressed by liver macrophages in steady state and increased in TAMs. High expression of OXCT1 in macrophages is associated with poor survival of HCC patients. In mouse models of liver cancer, we found that OXCT1-deficiency in macrophages suppressed tumor growth. OXCT1 deficiency reprogramed TAMs towards an antitumoral phenotype, reduced CD8+ T cell exhaustion, and enhanced CD8+ T cell cytotoxicity. Mechanistically, upregulated OXCT1 expression in TAMs resulted in enhanced ketone metabolism and succinate generation, which promoted H3K4 trimethylation (H3K4me3) around Arg1 promoter and subsequent increased expression of Arg1. Supplement of ß-Hydroxybutyrate, acetoacetate or succinate also resulted in increased Arg1 expression. OXCT1 deficiency in TAMs resulted in decreased succinate level, decreased H3K4me3 of Arg1 promoter and Arg1 expression. Finally, we found that Pimozide, an inhibitor of OXCT1, could suppress the polarization of TAMs, leading to decreased immune suppression and suppressed tumor growth. In conclusion, our study demonstrates that ketone metabolism promotes TAM polarization and inhibiting ketone metabolism in TAMs is an effective approach for treating liver cancer.