Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.

中文翻译：

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色氨酸代谢和信号在癌症中的分子机制和治疗意义


色氨酸 （Trp） 代谢涉及三个主要途径：犬尿氨酸 （Kyn） 途径 （KP）、5-羟色胺（血清素，5-HT）途径和吲哚途径。在正常生理条件下，Trp 代谢在调节炎症、免疫和神经元功能方面起着至关重要的作用。吲哚胺-2,3-双加氧酶 （IDO）、Trp-2,3-双加氧酶 （TDO） 和犬尿氨酸单加氧酶 （KMO） 等关键限速酶驱动这些代谢过程。Trp 代谢失衡与各种癌症有关，并且通常与不良预后和不良临床特征相关。失调的 Trp 代谢主要通过产生免疫抑制性肿瘤微环境 （TME） 来促进肿瘤生长和免疫逃逸。KP 的激活导致免疫抑制代谢物（如 Kyn）的产生，Kyn 主要通过与芳烃受体 （AHR） 的相互作用来调节免疫反应并促进肿瘤发生。靶向 Trp 代谢的治疗性已显示出巨大的潜力，特别是随着 IDO1、TDO 和其他关键酶的小分子抑制剂的开发。这些抑制剂会破坏 TME 内的免疫抑制信号，从而可能恢复有效的抗肿瘤免疫反应。最近，IDO1 抑制剂已在临床试验中进行了测试，显示出增强现有癌症疗法效果的潜力。然而，后期试验的混合结果强调了更深入地了解 Trp 代谢及其在癌症中的复杂作用的必要性。最近的进展还探索了将 Trp 代谢抑制剂与其他治疗方法（如免疫检查点抑制剂、化疗和放疗）相结合，以增强治疗效果并克服耐药机制。 本文总结了目前对癌症中 Trp 代谢和信号传导的理解，详细介绍了 Trp 代谢失调的致癌机制和临床意义。此外，它还提供了对开发 Trp 靶向疗法的挑战以及旨在优化这些治疗策略和改善患者预后的未来研究方向的见解。