AUTHOR=Al-Zoubi Raed M. , Elaarag Mai , Al-Qudimat Ahmad R. , Al-Hurani Enas A. , Fares Zainab E. , Farhan Ala’a , Al-Zoubi Sally R. , Khan Abbas , Agouni Abdelali , Shkoor Mohanad , Bawadi Hiba , Zakaria Zain Z. , Al Zoubi Mazhar , Alrumaihi Khalid 

TITLE=IDO and TDO inhibitors in cancer immunotherapy: mechanisms, clinical development, and future directions

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1632446

DOI=10.3389/fphar.2025.1632446

ISSN=1663-9812

ABSTRACT=Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) inhibitors are promising avenues in cancer immunotherapy. These enzymes are key regulators in the kynurenine pathway. modulating immune responses and enabling tumor immune evasion. By targeting IDO and TDO. Therapeutic approaches aim to restore immune surveillance and enhance antitumor activity. This review examines the mechanisms of IDO/TDO in cancer etiology, their consequences in the tumor microenvironment, and the therapeutic development of inhibitors currently being studied. Among these, medications like Indoximod, Epacadostat, and Navoximod have shown promise in influencing the immune system and slowing tumor progression, while dual inhibitors like HTI-1090 try to address broader metabolic connections. Despite tremendous progress, obstacles like tumor heterogeneity, off-target consequences, and varying patient responses remain. The use of IDO/TDO inhibitors with conventional anticancer medications demonstrates their potential to reshape cancer treatment paradigms, contingent on further research to optimize efficacy and safety.Clinical Trial Registration:https://clinicaltrials.gov/study/NCT03844438.