Open Access

REVIEW

Emerging Role of ACOD1/Itaconate in Cancer: Bridging Metabolic Reprogramming and Signaling in the Tumor Microenvironment

Xing-Guo Li^1,2,3,#, Lu-Kai Wang^4,#, Fu-Ming Tsai⁵, Hsueh-Chun Wang^1,*

1 Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
2 Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
3 Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan
4 National Center for Biomodels, National Institutes of Applied Research, Taipei, Taiwan
5 Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan

* Corresponding Authors: Hsueh-Chun Wang. Email: ,
# These authors contributed equally to this work

(This article belongs to the Special Issue: Natural and Synthetic Small Molecules in the Regulation of Immune Cell Functions)

BIOCELL 2026, 50(6), 4 https://doi.org/10.32604/biocell.2026.075492

Received 02 November 2025; Accepted 23 January 2026; Issue published 09 June 2026

Abstract

Itaconate, produced by aconitate decarboxylase 1 (ACOD1, also known as IRG1), acts as a key immunometabolite that inhibits succinate dehydrogenase (SDH) and can engage reduction-oxidation (redox)-sensitive signaling programs. This review summarizes the emerging, context-dependent roles of the ACOD1-itaconate axis in cancer, while critically distinguishing between the effects of endogenous itaconate and its cell-permeable derivatives. In tumor cells, endogenous ACOD1 expression or uptake via solute carrier family 13 member 3 (SLC13A3) alters oxidative phosphorylation and glycolysis. In the tumor microenvironment, myeloid-derived itaconate contributes to immune tolerance by reducing dendritic-cell cross-priming and limiting CD8⁺ T-cell metabolic activity. Moreover, interactions between ACOD1-derived endogenous itaconate and stress-responsive signaling pathways, including Extracellular Signal-Regulated Kinase (ERK)1/2 and AMP-activated Protein Kinase (AMPK), couple mitochondrial metabolic perturbation to adaptive cellular responses, whereas electrophilic itaconate derivatives can additionally engage ERK- and Nuclear Factor Erythroid 2-related factor 2 (NRF2)-linked cytoprotective programs. Collectively, these findings highlight the ACOD1/itaconate axis as a context-dependent node of metabolic control, offering new perspectives for a stratified therapeutic approach based on tumor lineage and transporter expression.

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Keywords

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