Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
Open accessAbstract
Control of cellular metabolism is critical for efficient cell function, although little is known about the interplay between cell subset-specific metabolites in situ, especially in the tumor setting. Here, we determined how a macrophage-specific (Mϕ-specific) metabolite, itaconic acid, can regulate tumor progression in the peritoneum. We show that peritoneal tumors (B16 melanoma or ID8 ovarian carcinoma) elicited a fatty acid oxidation-mediated increase in oxidative phosphorylation (OXPHOS) and glycolysis in peritoneal tissue-resident macrophages (pResMϕ). Unbiased metabolomics identified itaconic acid, the product of immune-responsive gene 1-mediated (Irg1-mediated) catabolism of mitochondrial cis-aconitate, among the most highly upregulated metabolites in pResMϕ of tumor-bearing mice. Administration of lentivirally encoded Irg1 shRNA significantly reduced peritoneal tumors. This resulted in reductions in OXPHOS and OXPHOS-driven production of ROS in pResMϕ and ROS-mediated MAPK activation in tumor cells. Our findings demonstrate that tumors profoundly alter pResMϕ metabolism, leading to the production of itaconic acid, which potentiates tumor growth. Monocytes isolated from ovarian carcinoma patients' ascites fluid expressed significantly elevated levels of IRG1. Therefore, IRG1 in pResMϕ represents a potential therapeutic target for peritoneal tumors.
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Fumarate can bind reactive thiol residues and inactivate KEAP1, leading to an antioxidant response.
“The first insights into the relevance of succination in HRLCC patients was proposed in 2011, when it was shown that fumarate could bind reactive thiol residues and inactivate KEAP1, the negative regulator of the master antioxidant transcription factor Nrf2, leading to a powerful antioxidant response81,82”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [81]
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References 55 · Cited by 267
- Authors
- Weiss, J. M., Davies, L. C., Karwan, M., Ileva, L., Ozaki, M. K., Cheng, R. Y. S., Ridnour, L. A., Annunziata, C. M., Wink, D. A., & McVicar, D. W.
- Affiliations
- National Cancer Institute (US)
- Cardiff University (GB)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- McVicar, Daniel W.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-07-30
- Volume
- 128
- Issue
- 9
- Pages
- 3794-3805
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6118601
- OpenAlex
- W2808751821
- Cited by
- 267
- References
- 55
- Citations by year
- 2026: 25 · 2025: 30 · 2024: 50 · 2023: 45 · 2022: 29 · 2021: 37 · 2020: 26 · 2019: 21 · 2018: 4
- FWCI
- 9.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Funders
- National Cancer Institute (Intramural Research Program)
- Wellcome Trust (WT10393MA)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- itaconic acid, IRG1, peritoneal macrophages, tumor-associated macrophages, peritoneal tumors, fatty acid oxidation, oxidative phosphorylation, glycolysis, reactive oxygen species, MAPK signaling, B16 melanoma, tumor microenvironment metabolism, therapeutic target
- MeSH terms
- Animals, Carboxy-Lyases, Fatty Acids, Female, Glycolysis, Humans, Hydro-Lyases, Melanoma, Experimental, Mice, Inbred C57BL, Monocytes, Ovarian Neoplasms, Oxidative Phosphorylation, Peritoneal Neoplasms, Proteins, Succinates, Reactive Oxygen Species, Macrophages, Peritoneal, Mice, Knockout, Disease Progression, RNA, Small Interfering, Cell Line, Tumor, Tumor Burden, Mice
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