Role of tryptophan metabolism in cancers and therapeutic implications

Tryptophan (Trp) metabolism is associated with diverse biological processes, including nerve conduction, inflammation, and the immune response. The majority of free Trp is broken down through the kynurenine (Kyn) pathway (KP), in which indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) catalyze the rate-limiting step. Clinical studies have demonstrated that Trp metabolism promotes tumor progression due to modulation of the immunosuppressive microenvironment through multiple mechanisms. In this process, IDO-expressing dendritic cells (DCs) exhibit tolerogenic potential and orchestrate T cell immune responses. Various signaling molecules control IDO expression, initiating the immunoregulatory pathway of Trp catabolism. Based on these characteristics, KP enzymes and catabolites are emerging as significant prognostic indicators and potential therapeutic targets of cancer. The physiological and oncologic roles of Trp metabolism are briefly summarized here, along with great challenges for treatment strategies. (C) 2021 Published by Elsevier B.V.