对免疫检查点抑制剂（ICI）反应的个体差异仍然是癌症治疗的主要挑战。肠道微生物组的组成与不同的 ICI 结果相关，但潜在的分子机制仍不清楚，治疗调节具有挑战性。我们建立了一个体内模型，用 I 型干扰素 (IFN-I) 治疗 C57Bl/6j 小鼠-调节细菌衍生的代谢物脱氨酪氨酸 (DAT)，以改善 ICI 治疗。广谱抗生素被用来模拟肠道微生物失调和相关的 ICI 耐药性。我们利用遗传小鼠模型来研究宿主 IFN-I 在 DAT 调节的抗肿瘤免疫中的作用。使用 16S-rRNA 测序分析评估肠道微生物群的变化。我们发现给小鼠口服补充微生物代谢物 DAT 可以延缓肿瘤生长，并促进抗 CTLA-4 或抗 PD-1 的 ICI 免疫治疗。 DAT 增强的抗肿瘤免疫力与肿瘤微环境中更多活化的 T 细胞和自然杀伤细胞相关，并且依赖于宿主 IFN-I 信号传导。与此一致的是，在接种 IFN-I 诱导佐剂后，DAT 有效增强了抗原特异性 T 细胞的扩增。小鼠补充 DAT 可以补偿广谱抗生素引起的生态失调对抗 CTLA-4 介导的抗肿瘤免疫的负面影响。口服 DAT 改变了小鼠的肠道微生物组成，增加了细菌分类群的丰度，这些细菌分类群与 ICI 免疫疗法的有益反应相关。我们介绍了使用 IFN-I 调节细菌衍生代谢物来克服 ICI 耐药性的治疗用途。这种方法是一种很有前途的策略，特别是对于有广谱抗生素使用史和相关肠道微生物多样性丧失的患者。黑色素瘤研究联盟、德国研究联盟、德国癌症援助组织、威廉·桑德基金会、诺华基金会。版权所有 © 2023 作者（ s）。由 Elsevier B.V. 出版。保留所有权利。

Inter-individual differences in response to immune checkpoint inhibitors (ICI) remain a major challenge in cancer treatment. The composition of the gut microbiome has been associated with differential ICI outcome, but the underlying molecular mechanisms remain unclear, and therapeutic modulation challenging.We established an in vivo model to treat C57Bl/6j mice with the type-I interferon (IFN-I)-modulating, bacterial-derived metabolite desaminotyrosine (DAT) to improve ICI therapy. Broad spectrum antibiotics were used to mimic gut microbial dysbiosis and associated ICI resistance. We utilized genetic mouse models to address the role of host IFN-I in DAT-modulated antitumour immunity. Changes in gut microbiota were assessed using 16S-rRNA sequencing analyses.We found that oral supplementation of mice with the microbial metabolite DAT delays tumour growth and promotes ICI immunotherapy with anti-CTLA-4 or anti-PD-1. DAT-enhanced antitumour immunity was associated with more activated T cells and natural killer cells in the tumour microenvironment and was dependent on host IFN-I signalling. Consistent with this, DAT potently enhanced expansion of antigen-specific T cells following vaccination with an IFN-I-inducing adjuvant. DAT supplementation in mice compensated for the negative effects of broad-spectrum antibiotic-induced dysbiosis on anti-CTLA-4-mediated antitumour immunity. Oral administration of DAT altered the gut microbial composition in mice with increased abundance of bacterial taxa that are associated with beneficial response to ICI immunotherapy.We introduce the therapeutic use of an IFN-I-modulating bacterial-derived metabolite to overcome resistance to ICI. This approach is a promising strategy particularly for patients with a history of broad-spectrum antibiotic use and associated loss of gut microbial diversity.Melanoma Research Alliance, Deutsche Forschungsgemeinschaft, German Cancer Aid, Wilhelm Sander Foundation, Novartis Foundation.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.