IL4i1-sourced oncometabolites promote neuroblastoma cell survival

High-risk neuroblastoma (NB) is driven by the amplification of MYCN in conjunction with additional oncogenic mutations in kinases such as ALK. NB cells require antioxidant responses to maintain redox balance and are highly sensitive to ferroptosis. Here, we show that metabolites derived from infiltrating immune cells expressing IL4i1, a secreted oxidoreductase, are potent suppressors of NB ferroptosis. IL4i1 metabolites (indole-3-pyruvate and 4-hydroxyphenylpyruvate) blocked ferroptosis in all human NB cell lines via a mechanism that depended on free radical scavenging and NRF2 activation but did not require the aryl hydrocarbon receptor. Supernatant transfer experiments confirmed that IL4i1 creates a milieu that protects NB cells from oxidative cell death. Importantly, mice lacking IL4i1 were protected from NB in a high-penetrance MYCN and mutant ALK-driven autochthonous cancer model. Therefore, we propose that immune IL4i1 is permissive for NB growth and survival. IL4i1 produces context-dependent oncometabolites and, as a secreted enzyme, represents a target for cell death manipulation in cancers sensitive to oxidative stress-driven cell death. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/669062v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@6e79baorg.highwire.dtl.DTLVardef@f9a9bcorg.highwire.dtl.DTLVardef@f6b2aaorg.highwire.dtl.DTLVardef@4bb764_HPS_FORMAT_FIGEXP M_FIG C_FIG