Li Xiuyun, Meng Hao, Wang Hefeng, Zhang Yujing, Yu Wanpeng
Infection and Microbiology Research Laboratory for Women and Children, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, Shandong, China.
The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, China.
Front Pharmacol. 2025 Aug 12;16:1640073. doi: 10.3389/fphar.2025.1640073. eCollection 2025.
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: GCN2-mediated 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.
吲哚胺2,3-双加氧酶1（IDO1）已成为癌症中一种关键的免疫代谢调节因子，通过其将色氨酸限速分解为犬尿氨酸来协调免疫抑制。这种酶活性通过两条不同途径建立免疫抑制性肿瘤微环境：色氨酸耗竭导致的GCN2介导的T细胞无反应性，以及犬尿氨酸代谢产物积累诱导的芳烃受体（AhR）依赖性免疫耐受。IDO1抑制的治疗格局已从早期的血红素竞争性抑制剂（如依帕司他）显著发展到下一代靶向蛋白水解嵌合体（PROTAC）技术。虽然超过20种小分子IDO1抑制剂已进入针对各种癌症的临床试验，但其疗效的差异凸显了改进靶点结合策略和更好的患者选择生物标志物的必要性。PROTAC代表了IDO1调节的范式转变，具有完全降解靶点而非仅仅抑制的独特优势。本综述系统评估：（1）临床研究的IDO1抑制剂及其药理学特征，以及（2）靶向IDO1的PROTAC降解剂的临床前前景。通过对其作用机制和治疗潜力的批判性分析，我们为优化癌症免疫治疗的IDO1靶向策略提供了见解。
