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Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis

Significant progress has been made in cancer immunotherapy with checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)–programmed death-ligand 1 signaling pathways. Tumors from patients showing sustained treatment response predominately demonstrate a T cell–inflamed tumor microenvironment prior to, or early on, treatment. Not all tumors with this phenotype respond, however, and one mediator of immunosuppression in T cell–inflamed tumors is the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) pathway. Multiple mechanisms of immunosuppression may be mediated by this pathway including depletion of tryptophan, direct immunosuppression of Kyn, and activity of Kyn-bound AhR. Indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in Trp catabolism, is the target of small-molecule inhibitors in clinical development in combination with PD-1 checkpoint inhibitors. Despite promising results in early-phase clinical trials in a range of tumor types, a phase III study of the IDO1-selective inhibitor epacadostat in combination with pembrolizumab showed no difference between the epacadostat-treated group versus placebo in patients with metastatic melanoma. This has led to a diminution of interest in IDO1 inhibitors; however, other approaches to inhibit this pathway continue to be considered. Novel Trp–Kyn–AhR pathway inhibitors, such as Kyn-degrading enzymes, direct AhR antagonists, and tryptophan mimetics are advancing in early-stage or preclinical development. Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp–Kyn–AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.