Exploding interest in immunometabolism as a source of new
cancer therapeutics has been driven in large part by studies of
tryptophan catabolism mediated by IDO/TDO
enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in
cancers where it blunts immunosurveillance and enables neovascularization and
metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the
enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1
enzyme. However, clinical development focused on D-1MT (now termed
indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1,
indoximod acts downstream of IDO1 to stimulate
mTORC1, a convergent effector signaling molecule for all IDO/TDO
enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique
biological and mechanistic features of
indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of
cancer therapy, including
chemotherapy, chemo-
radiotherapy,
vaccines, and immune checkpoint
therapy. We also review the potential advantages
indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by
tumors.
Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to
vaccine adjuvants that act to boost immunity in settings of
infectious disease.