The XOR-IDH3α axis controls macrophage polarization in hepatocellular carcinoma

Background & Aims: Tumor-associated macrophages (TAMs) are indispensable in the hepatocellular carcinoma (HCC) tumor microenvironment. Xanthine oxidoreductase (XOR), also known as xanthine dehydrogenase (XDH), participates in purine metabolism, uric acid production, and macrophage polarization to a pro-inflammatory phenotype. However, the role of XOR in HCC-associated TAMs is unclear.Methods: We evaluated the XOR level in macrophages isolated from HCC tissues and paired adjacent tissues. We established diethylnitrosamine/carbon tetrachloride (CCl4)-induced and orthotopically implanted HCC mouse models using mice with Xdh-specific depletion in the myeloid cell lineage (Xdh(f/f)Lyz2(cre)) or Kupffer cells (Xdh(f/f)Clec4f(cre)). We determined metabolic differences using specific methodologies, including metabolomics and metabolic flux.Results: We found that XOR expression was downregulated in HCC TAMs and positively correlated with patient survival, which was strongly related to the characteristics of the tumor microenvironment, especially hypoxia. Using HCC-inflicted mice (Xdh(f/f)Lyz2(cre) and Xdh(f/f)Clec4f(cre)), we revealed that XOR loss in monocyte-derived TAMs rather than Kupffer cells promoted their M2 polarization and CD8(+) T-cell exhaustion, which exacerbated HCC progression. In addition, the tricarboxylic acid cycle was disturbed, and the generation of alpha-ketoglutarate was enhanced within XOR-depleted macrophages. XOR inhibited alpha-ketoglutarate production by interacting with IDH3 alpha catalytic sites (K142 and Q139). The increased IDH3 alpha activity caused increased adenosine and kynurenic acid production in TAMs, which enhanced the immunosuppressive effects of TAMs and CD8(+) T cells.Conclusions: The XOR-IDH3 alpha axis mediates TAM polarization and HCC progression and may be a small-molecule therapeutic or immunotherapeutic target against suppressive HCC TAMs.(c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Automated summary

This study found that XOR expression is downregulated in hepatocellular carcinoma (HCC), and XOR loss in monocyte-derived tumor-associated macrophages (TAMs) promotes their polarization and CD8(+) T-cell exhaustion, exacerbating HCC progression. XOR depletion also disrupts the tricarboxylic acid cycle and increases adenosine and kynurenic acid production in TAMs, enhancing their immunosuppressive effects. The XOR-IDH3 alpha axis may serve as a therapeutic target against suppressive HCC TAMs.