An enzyme-responsive nanoplatform rewires host-microbe tryptophan metabolism for cancer immunotherapy

IF 23.2 1区医学 Q1 MICROBIOLOGY

Cell host & microbe Pub Date : 2026-09-30 DOI:10.1016/j.chom.2026.09.011

Chao Pan, Taotao Zhou, Liqin Ye, Canyu Yang, Qinyu Li, Hongyu Liu, Fenqing Tang, Gulixian Aili, Shidong Zhou, Yong Gan

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引用次数: 0

Abstract

Immunotherapy shows great promise against cancer, yet imbalanced tryptophan (Trp) metabolism drives tumor immune tolerance, severely limiting its efficacy. To address this, we advance a synergistic host-microbe metabolism-regulated strategy that concurrently amplifies microbial indole pathway while suppressing the host kynurenine (Kyn) pathway to correct metabolic and immune dysregulation, thereby enhancing antitumor immunity. To produce an oral co-delivery nanoparticle, mesoporous silica nanoparticles are loaded with Trp via ester bonds and coated with agar containing the metabolism inhibitor NLG919 (NLG). This design enables enzyme-responsive release of Trp and NLG in the large intestine, where microbiota and colorectal tumors coexist. Unlike conventional strategies that either block the Kyn pathway or non-selectively activate both pathways, this platform enhances Trp metabolism toward immunostimulatory microbial indole derivatives while suppressing the immunosuppressive Kyn pathway, thereby synergistically enhancing antitumor immunity and achieving potent efficacy with favorable biosafety, offering a promising metabolism-guided paradigm for safe and effective cancer immunotherapy.

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酶反应纳米平台重新连接宿主-微生物色氨酸代谢用于癌症免疫治疗

免疫治疗显示出抗癌的巨大前景，但色氨酸代谢失衡导致肿瘤免疫耐受，严重限制了其疗效。为了解决这个问题，我们提出了一种协同宿主-微生物代谢调节策略，该策略在抑制宿主犬尿氨酸（Kyn）途径的同时放大微生物吲哚途径，以纠正代谢和免疫失调，从而增强抗肿瘤免疫。为了制备口服共递送纳米颗粒，介孔二氧化硅纳米颗粒通过酯键装载色氨酸，并涂覆含有代谢抑制剂NLG919 （NLG）的琼脂。这种设计使Trp和NLG在大肠中酶反应释放，在大肠中微生物群和结直肠肿瘤共存。与传统阻断Kyn途径或非选择性激活这两种途径的策略不同，该平台在抑制免疫抑制Kyn途径的同时，增强了色氨酸对免疫刺激微生物吲哚衍生物的代谢，从而协同增强抗肿瘤免疫，并获得了良好的生物安全性，为安全有效的癌症免疫治疗提供了一个有希望的代谢指导范式。

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来源期刊

Cell host & microbe 生物-微生物学

CiteScore

45.10

自引率

1.70%

发文量

201

审稿时长

4-8 weeks

期刊介绍： Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.