Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the kynurenine (KYN) metabolic pathway. Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase general control nonderepressible 2 (GCN2). Emerging data have shed light on an unexpected role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in transducing the tumor immune escape function imparted by IDO1 and TDO2. AhR activation by the IDO1/TDO2 product KYN leads to the generation of immune-tolerant dendritic cells (DCs) and regulatory T cells, which collectively foster a tumor immunological microenvironment that is defective in recognizing and eradicating cancer cells. Multiple IDO1 inhibitors have been evaluated in clinical trials. There are novel modalities downstream of IDO1/TDO2 for pharmacological interventions. We review recent progress and future perspectives in targeting the IDO1/TDO2–KYN–AhR signaling pathway for the development of novel cancer immunotherapies.

吲哚胺2,3-双加氧酶1（IDO1）和色氨酸2,3-双加氧酶2（TDO2）催化犬尿氨酸（KYN）代谢途径的承诺步骤。传统上，IDO1的免疫抑制作用主要归因于色氨酸水平降低，色氨酸水平激活了激酶的总体控制不可抑制2（GCN2）。新兴数据揭示了配体激活的转录因子芳烃受体（AhR）在转导IDO1和TDO2赋予的肿瘤免疫逃逸功能方面的出乎意料的作用。IDO1 / TDO2产物KYN的AhR激活导致产生免疫耐受的树突状细胞（DC）和调节性T细胞，它们共同促进了在识别和根除癌细胞方面存在缺陷的肿瘤免疫微环境。多种IDO1抑制剂已在临床试验中进行了评估。在IDO1 / TDO2下游有新的药理干预手段。我们回顾了针对IDO1 / TDO2-KYN-AhR信号通路开发新型癌症免疫疗法的最新进展和未来观点。