RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
微生物脂质-ATP 合酶轴驱动 NK 细胞抗肿瘤活性
英文原题：A Microbial Lipid-ATP Synthase Axis Fuels NK Cell Antitumor Activity.
查看英文原题
A Microbial Lipid-ATP Synthase Axis Fuels NK Cell Antitumor Activity.
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中文摘要
肠道微生物群通过器官间通讯影响全身免疫和癌症，但 OMV 介导的机制仍不清楚。在此，我们揭示了 Bacteroides intestinalis 一种此前未被认识的作用，即通过富含鞘氨醇（SP）的 OMV 抑制肠外肿瘤生长；SP 是一种生物活性脂质，可直接结合 ATP5F1A——线粒体 ATP 合酶的 α 亚基——从而增强 NK 细胞功能。这种微生物脂质-ATP 合酶相互作用可提高线粒体效率，减少活性氧（ROS）生成，并有效上调 NK 细胞中 IFN- 的分泌，进而驱动细胞毒性和肿瘤浸润增加。值得注意的是，来自 B. intestinalis 的 OMV 或 SP 给药可显著抑制小鼠肿瘤生长，而它们与抗 PD-1 治疗联合可增强全身抗肿瘤免疫。本研究确立了肠道微生物 OMV 的特异性免疫激活能力，并凸显了微生物群来源的脂质免疫疗法。
展开英文摘要原文
The gut microbiota influences systemic immunity and cancer through inter-organ communication, but OMV-mediated mechanisms remain unclear.
Here, we uncover a previously unrecognized role of Bacteroides intestinalis in restraining extra-intestinal tumor growth via OMVs enriched in sphingosine (SP), a bioactive lipid that directly binds to ATP5F1A-a subunit of the mitochondrial ATP synthase-to enhance NK cell function.
This microbial lipid-ATP synthase interaction augments mitochondrial efficiency, reduces reactive oxygen species (ROS) production, and potently upregulates IFN- secretion in NK cells, driving increased cytotoxicity and tumor infiltration. Remarkably, OMVs from B. intestinalis or SP administration greatly inhibit murine tumor growth, while their combination with anti-PD-1 therapy enhances systemic antitumor immunity.
This study establishes the specific immune activation ability for gut microbial OMVs and highlights microbiota-derived lipid-based immunotherapies.
论文信息
- 作者
- Yu K、Sun X、Ma W、Yang J、Sun X、Zhang L、Liu Y、Ren T
- 第一作者单位
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, State Key Laboratory of Experimental Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.China
- 通讯作者单位
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Experimental Hematology, Beijing, China.China
- 期刊
- Advanced science (Weinheim, Baden-Wurttemberg, Germany)2026 Jul
- 原文标识
- PubMed 41972457 · DOI 10.1002/advs.202520095
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