Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

l-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases. Imbalances in the kynurenine pathway (KP) of tryptophan metabolism are associated with CNS disorders, infectious diseases, autoimmune diseases and cancer, highlighting KP enzymes as potential therapeutic targets. Here, Platten and colleagues provide an overview of the physiological and pathophysiological roles of tryptophan metabolism, focusing on the clinical potential and challenges associated with targeting this pathway.