ZFTA–RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA–RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA–RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA–RELA levels. Itaconate epigenetically activates ZFTA–RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA–RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA–RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA–RELA epigenetically suppresses PTEN expression to upregulate PI3K–mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K–mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA–RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA–RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA–RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA–RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.
