Itaconate acts as an oncometabolite to drive lethal pediatric ependymomas

ZFTA-RELA ependymomas are highly aggressive brain tumors with significant mortality. These tumors are characterized by the oncogenic fusion of a putative chromatin remodeler ZFTA and the NFκB effector RELA. Using a comprehensive metabolic screen, we discovered that ZFTA-RELA cells generate itaconate, a metabolite linked to the TCA cycle. Although itaconate is a well-known immunomodulatory metabolite produced by macrophages, its production and function within tumor cells have been unclear. We found that itaconate is synthesized by Aconitate Decarboxylase-1 (ACOD1), and that ZFTA-RELA induces ACOD1 expression in an NFκB-dependent manner. Itaconate production in turn supports a coupled metabolic-epigenetic feed-forward loop that sustains pathogenic ZFTA-RELA fusion expression through H3K4me3-dependent, epigenetic activation. To provide the metabolic input required for itaconate synthesis, ZFTA-RELA tumors suppress PTEN expression to activate PI3K/AKT signaling pathway. The increased glutaminolysis in these tumors supplied the carbon needed for itaconate generation. As a result, inhibiting glutamine metabolism reduces pathogenic ZFTA-RELA levels and shows strong therapeutic efficacy in multiple in vivo models. Moreover, combining glutamine antagonists with PI3K/mTOR inhibitors prevents spinal metastasis. Overall, our findings show that ZFTA-RELA ependymomas hijack the macrophage-associated itaconate metabolic pathway to epigenetically reinforce expression of the ZFTA-RELA fusion driver, identifying itaconate as an oncometabolite. These results highlight itaconate upregulation as an unrecognized driver of ZFTA-RELA ependymoma and point to new therapeutic avenues for children affected by this devastating disease, while broadening our understanding of oncometabolites as a distinct class of cancer dependencies.