REVIEW article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1640073
Indoleamine 2,3-Dioxygenase 1 in Cancer Immunotherapy: From Small-Molecule Inhibition to PROTAC-Mediated Degradation
Provisionally accepted
- 1Shandong Province Maternal and Child Health Care Hospital, Jinan, China
- 2Qingdao University, Qingdao, China
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Indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as a critical immunometabolic regulator in cancer, orchestrating immunosuppression through its rate-limiting catabolism of tryptophan to kynurenine. This enzymatic activity establishes an immunosuppressive tumor microenvironment via two distinct pathways: GCN2mediated T cell anergy resulting from tryptophan depletion, and AhR-dependent immune tolerance induced by accumulating kynurenine metabolites. The therapeutic landscape of IDO1 inhibition has progressed significantly from early heme-competitive inhibitors like epacadostat to next-generation proteolysis-targeting chimera (PROTAC) technology. While over 20 small-molecule IDO1 inhibitors have entered clinical trials for various cancers, their variable efficacy has underscored the need for improved target engagement strategies and better patient selection biomarkers. PROTACs represent a paradigm shift in IDO1 modulation, offering the unique advantage of complete target degradation rather than mere inhibition. This review systematically evaluates: (1) clinically investigated IDO1 inhibitors and their pharmacological profiles, and (2) the preclinical promise of IDO1-targeting PROTAC degraders. Through critical analysis of their mechanisms of action and therapeutic potential, we provide insights into optimizing IDO1-targeted strategies for cancer immunotherapy.
Keywords: IDO1, Small-molecule inhibitors, PROTACs, Protein degradation, cancer immunotherapy
Received: 03 Jun 2025; Accepted: 31 Jul 2025.
Copyright: © 2025 Li, Meng, Wang, Zhang and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wanpeng Yu, Qingdao University, Qingdao, China
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