肿瘤代谢的重编程对有效的免疫治疗提出了重大挑战，在发展免疫抑制微环境中发挥着至关重要的作用。特别是，吲哚胺吡咯 2,3-双加氧酶 1 (IDO1) 将氨基酸 L-色氨酸 (Trp) 降解为犬尿氨酸 (Kyn) 是临床上最有效的免疫抑制途径之一。因此，通过 IDO1 抑制调节 Trp/Kyn 代谢是增强免疫治疗的一种有前景的策略。在此，通过金属配位驱动组装 IDO1 抑制剂 (NLG919) 和干扰素基因刺激剂 (STING) 激动剂 (MSA-2) 来制备代谢调节纳米颗粒，用于增强免疫治疗。静脉注射后，组装的纳米颗粒可以在肿瘤中有效积聚，增强NLG919的生物利用度并下调Trp到Kyn的代谢，从而重塑免疫抑制的肿瘤微环境。同时，释放的 MSA-2 在肿瘤中引发有效的 STING 通路激活，引发有效的免疫反应。纳米颗粒诱导的抗肿瘤免疫显着抑制原发性和转移性肿瘤以及 B16 黑色素瘤的发展。总的来说，这项研究为通过协同氨基酸代谢和 STING 通路激活增强肿瘤免疫治疗提供了新的范例。版权所有 © 2024 Xiuying Duan 等人。

The reprogramming of tumor metabolism presents a substantial challenge for effective immunotherapy, playing a crucial role in developing an immunosuppressive microenvironment. In particular, the degradation of the amino acid L-tryptophan (Trp) to kynurenine (Kyn) by indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) is one of the most clinically validated pathways for immune suppression. Thus, regulating the Trp/Kyn metabolism by IDO1 inhibition represents a promising strategy for enhancing immunotherapy. Herein, metabolism-regulated nanoparticles are prepared through metal coordination-driven assembly of an IDO1 inhibitor (NLG919) and a stimulator of interferon genes (STING) agonist (MSA-2) for enhanced immunotherapy. After intravenous administration, the assembled nanoparticles could efficiently accumulate in tumors, enhancing the bioavailability of NLG919 and down-regulating the metabolism of Trp to Kyn to remodel the immunosuppressive tumor microenvironment. Meanwhile, the released MSA-2 evoked potent STING pathway activation in tumors, triggering an effective immune response. The antitumor immunity induced by nanoparticles significantly inhibited the development of primary and metastatic tumors, as well as B16 melanoma. Overall, this study provided a novel paradigm for enhancing tumor immunotherapy through synergistic amino acid metabolism and STING pathway activation.Copyright © 2024 Xiuying Duan et al.