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
BPTF 特异性 PROTAC 降解剂增强基于 NK 细胞的肿瘤免疫治疗
英文原题：A BPTF-specific PROTAC degrader enhances NK cell-based cancer immunotherapy.
查看英文原题
A BPTF-specific PROTAC degrader enhances NK cell-based cancer immunotherapy.
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中文摘要
自然杀伤（NK）细胞免疫疗法在癌症治疗中展现出前景，但其疗效仍然有限，亟需开发新的策略。在本研究中，我们证明表观遗传因子含溴结构域 PHD 指转录因子（BPTF）通过其 PHD 指解读 H3K4me3，阻碍 NK 细胞对肝细胞癌（HCC）的识别。我们构建了一种小分子蛋白水解靶向嵌合体（PROTAC），可选择性降解人和小鼠 BPTF。使用 PROTAC 降解 BPTF 可直接提高 HCC 细胞上自然细胞毒性受体配体的丰度，促进其被 NK 细胞识别，从而在体外和体内增强 NK 细胞对 HCC 的细胞毒性。通过多学科技术，我们的研究结果确立了以 PROTAC 靶向 BPTF 作为克服 HCC 逃避 NK 细胞免疫的一种有前景的方法，并提供了增强基于 NK 细胞的癌症免疫治疗的新策略。
展开英文摘要原文
Natural killer (NK) cell-based immunotherapy shows promise in cancer treatment, but its efficacy remains limited, necessitating the development of novel strategies. In this study, we demonstrate that the epigenetic factor bromodomain PHD-finger containing transcription factor (BPTF) hinders hepatocellular carcinoma (HCC) recognition by NK cells through its PHD finger's interpretation of H3K4me3.
We have generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degrades human and murine BPTF. The degradation of BPTF using PROTACs directly enhances the abundance of natural cytotoxicity receptor ligands on HCC cells, facilitating their recognition by NK cells and thereby augmenting NK cell cytotoxicity against HCC both in vitro and in vivo.
Through multidisciplinary techniques, our findings establish targeting BPTF with PROTACs as a promising approach to overcome immune evasion of HCC from NK cells and provide a new strategy to enhance NK cell-based cancer immunotherapy.
论文信息
- 作者
- Li Y、Bai L、Liang H、Yan P、Chen H、Cao Z、Shen Y、Wang Z
- 第一作者单位
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.China
- 通讯作者单位
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: wy83@ustc.edu.cn.China
- 期刊
- Molecular therapy : the journal of the American Society of Gene Therapy2025 Apr 2
- 原文标识
- PubMed 39935175 · DOI 10.1016/j.ymthe.2025.02.013
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