The ACOD1-itaconate axis in inflammation and cancer: immune regulation, context-dependent functions, and therapeutic challenges

Abstract Immunometabolism has emerged as a central framework for understanding how metabolic pathways regulate immune cell function and inflammatory responses. Among the metabolic programmes that shape innate immunity, the aconitate decarboxylase 1 (ACOD1) - itaconate axis has attracted considerable attention because of its ability to link inflammatory signalling with extensive metabolic reprogramming. ACOD1 is induced in myeloid cells following activation by pathogen- and damage-associated signals, leading to the conversion of cis-aconitate, a tricarboxylic acid (TCA) cycle intermediate, into itaconate. This metabolic rewiring interrupts the TCA cycle flux and influences the abundance of key metabolites, including α-ketoglutarate, succinate and fumarate, thereby affecting immune cell polarization and cytokine production. In this review, we summarize current knowledge regarding the regulation and biological functions of the ACOD1-itaconate axis in inflammation, infection and cancer. We discuss the signalling pathways responsible for ACOD1 induction, including Toll-like receptor, interferon and STING-mediated pathways, and highlight the antimicrobial properties of itaconate against bacterial and viral pathogens. We further examine the mechanisms through which endogenous itaconate and its derivatives regulate immune responses, including modulation of succinate dehydrogenase activity, redox homeostasis, NRF2 signalling, inflammasome activation, interferon responses and epigenetic regulation. We also focus on the role of the ACOD1-itaconate axis within the tumour microenvironment, where it influences macrophage polarization, T-cell function and anti-tumour immunity. Notably, ACOD1 and itaconate can exert both tumour-promoting and tumour-suppressive effects depending on cellular context, metabolic state and tumour type. These context-dependent functions underscore the complexity of this pathway and the need for a nuanced understanding of its biological roles. Lastly, we discuss current therapeutic strategies aimed at targeting ACOD1 activity or modulating itaconate signalling, as well as key challenges related to species-specific differences, discrete biological effects of endogenous itaconate versus synthetic derivatives and distinct itaconate-dependent from itaconate-independent mechanisms, including gene regulatory programs and protein activities. Collectively, the ACOD1-itaconate axis represents a pivotal immunometabolic node with significant implications for pathogenesis and therapy of inflammatory disorders, infectious diseases and cancer.