Tryptophan metabolism in tumor microenvironment and therapeutic implications

Tryptophan (Trp) catabolism has been recognized as a key immunosuppressive axis in cancer. However, this largely centered on indoleamine-2,3-dioxygenase 1 (IDO1). The clinical failure of IDO1 inhibitors has exposed the limitations of this reductionist view.

To re-synthesize current knowledge into a further understanding of Trp metabolism, and propose biomarker-guided, multi-node intervention strategies that can resurrect Trp metabolism as a precision immuno-oncology target. Key Scientific Concepts of Review: This review comprehensively describes the pathways of Trp metabolism in the human body and the key enzymes that can serve as therapeutic targets, thus proposing the possibility of multi enzyme combined inhibition. Second, we synthesize how Trp metabolites can modulate the functionality of immune cells, mainly T cells, within the tumor microenvironment, thereby affecting tumor immune surveillance and the efficacy of immunotherapy. Then we discuss how tumor cells manipulate Trp metabolic pathways to enhance their survival and metastasis. We also propose a new framework for targeting Trp metabolism, such as combining enzymes inhibitors or Aryl hydrocarbon receptor (AhR) antagonists with immune checkpoint blockade. By shifting from "IDO1-focus" paradigms to comprehensive metabolic interventions, we may release more potential of Trp modulation in cancer immunotherapy.