Molecular mechanisms and therapeutic significance of Tryptophan Metabolism and signaling in cancer.
Cancer
Clinical characteristics
Expression changes
Targeted therapies
Tryptophan metabolism
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
30 Oct 2024
30 Oct 2024
Historique:
received:
23
08
2024
accepted:
24
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.
Identifiants
pubmed: 39472902
doi: 10.1186/s12943-024-02164-y
pii: 10.1186/s12943-024-02164-y
doi:
Substances chimiques
Tryptophan
8DUH1N11BX
Kynurenine
343-65-7
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Tryptophan Oxygenase
EC 1.13.11.11
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
241Subventions
Organisme : the Excellent Youth Talent Cultivation Program of Innovation in Health Science and Technology of Henan Province
ID : YXKC2022061
Organisme : the China Postdoctoral Science Foundation
ID : 2024M752952
Organisme : the Henan Medical Science and Technology Joint Building Program
ID : LHGJ20230239
Organisme : China National Natural Science Foundation
ID : 82102149, 82472069, and 82401623
Informations de copyright
© 2024. The Author(s).
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