IL4i1 and IDO1: Oxidases that control a tryptophan metabolic nexus in cancer

Regulated tryptophan metabolism by immune cells has been associated with the promotion of tolerance and poor outcomes in cancer. The main focus of research has centered on local tryptophan depletion by IDO1, an intracellular heme-dependent oxidase that converts tryptophan to formyl-kynurenine. This is the first step of a complex pathway supplying metabolites for de novo NAD⁺ biosynthesis, 1-carbon metabolism, and a myriad of kynurenine derivatives of which several act as agonists of the arylhydrocarbon receptor (AhR). Thus, cells that express IDO1 deplete tryptophan while generating downstream metabolites. We now know that another enzyme, the secreted L-amino acid oxidase IL4i1 also generates bioactive metabolites from tryptophan. In tumor microenvironments, IL4i1 and IDO1 have overlapping expression patterns, especially in myeloid cells, suggesting the two enzymes control a network of tryptophan-specific metabolic events. New findings about IL4i1 and IDO1 have shown that both enzymes generate a suite of metabolites that suppress oxidative cell death ferroptosis. Thus, within inflammatory environments, IL4i1 and IDO1 simultaneously control essential amino acid depletion, AhR activation, suppression of ferroptosis, and biosynthesis of key metabolic intermediates. Here, we summarize the recent advances in this field, focusing on IDO1 and IL4i1 in cancer. We speculate that while inhibition of IDO1 remains a viable adjuvant therapy for solid tumors, the overlapping effects of IL4i1 must be accounted for, as potentially both enzymes may need to be inhibited at the same time to produce positive effects in cancer therapy.