Abstract: Indoleamine 2.3-dioxygenases (IDO1/2) and tryptophan 2.3-dioxygenase (TDO) are the initial and rate-limiting enzymes in tryptophan metabolism, which play an essential role in mediating immunosuppression in tumor microenvironment. Accumulating evidence has indicated that both IDO1 and TDO are highly expressed in many malignant tumors, and their expression is generally associated with reduced tumor-infiltrating immune cells, increased regulatory T-cell infiltration, as well as cancer progression and poor prognosis for malignancies. A large number of IDO1 and TDO inhibitors have been screened or synthesized in the last two decades. Thus far, at least 12 antagonists targeting IDO1 and TDO have advanced to clinical trials. In this account, we conducted a comprehensive review of the development of IDO1 and TDO inhibitors in cancer immunotherapy, particularly their clinical research progress, and presented the current challenges and corresponding solutions.

Keywords: indoleamine 2, 3-dioxygenase, tryptophan-2, 3-dioxygenase, tryptophan metabolism, cancer immunotherapy, immune tolerance


中文翻译：

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癌症免疫治疗中靶向吲哚胺双加氧酶和色氨酸双加氧酶：临床进展和挑战


摘要：吲哚胺2.3-双加氧酶（IDO1/2）和色氨酸2.3-双加氧酶（TDO）是色氨酸代谢的起始酶和限速酶，在介导肿瘤微环境中的免疫抑制中发挥重要作用。越来越多的证据表明，IDO1和TDO在许多恶性肿瘤中高表达，其表达通常与肿瘤浸润免疫细胞减少、调节性T细胞浸润增加以及癌症进展和恶性肿瘤预后不良有关。近二十年来，大量的IDO1和TDO抑制剂被筛选或合成。迄今为止，至少有 12 种针对 IDO1 和 TDO 的拮抗剂已进入临床试验。本文对IDO1和TDO抑制剂在癌症免疫治疗中的发展，特别是其临床研究进展进行了全面的回顾，并提出了目前面临的挑战和相应的解决方案。


关键词:吲哚胺 2, 3-双加氧酶, 色氨酸-2, 3-双加氧酶, 色氨酸代谢, 癌症免疫治疗, 免疫耐受