Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting step in the kynurenine pathway, which converts the essential amino acid tryptophan into kynurenine and other metabolites (Ball, 2014). This enzymatic activity exerts significant immunoregulatory effects, which has made it an attractive target for immunotherapy research.

IDO1, pictured here in A-431 cells, is expressed in various tissues and induced in antigen-presenting cells (APCs) like dendritic cells and macrophages by inflammatory signals such as interferon-gamma (IFN-γ). It exerts immunomodulatory effects through several mechanisms.

First, IDO1 reduces local tryptophan levels, which in addition to inhibiting the growth of internal pathogens also affects the viability of T cells, which require tryptophan to function (Lee, 2002).

Second, the metabolites produced in the kynurenine pathway, such as kynurenine itself, can bind to the aryl hydrocarbon receptor (AHR) on immune cells, promoting the differentiation of regulatory T cells (Tregs) which suppress immune responses (Stone, 2023).

Third, kynurenine metabolites appear to directly be able to inhibit the activity of cytotoxic T lymphocytes and natural killer cells, possibly by downregulating the surface expression of NKG2D, a key activating receptor (Fang, 2022).

Tumors are known to exploit IDO1's immunosuppressive properties by upregulating its expression, creating an environment that protects them from immune attack (Godin-Ethier, 2011). Theoretically, inhibiting IDO1 might therefore restore immune function and enhance the efficacy of cancer therapies like immune checkpoint inhibitors. Dozens of clinical trials have been set up to explore this, but despite pre-clinical successes, late-phase results have been disappointing in regards to both effect and toxicity (Fujiwara, 2022). Autoimmunity and upregulation of compensatory pathways via IDO2, a close relative of IDO1 with weaker enzymatic ability, and TDO, another tryptophan-degrading enzyme, have been cited as reasons (Merlo, 2020).

Despite this, interest in the pathway remains, and more recent therapeutic strategies aim to increase efficacy through dual inhibition and further explore the synergistic effects of IDO1 inhibition with other types of treatments (Chen, 2021).