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
组蛋白乳酰化驱动的瘤内 IGFBP2(+) NK 细胞促进肿瘤免疫逃逸
英文原题：Histone lactylation-driven intratumoral IGFBP2(+) NK cells promote tumor immune evasion.
查看英文原题
Histone lactylation-driven intratumoral IGFBP2(+) NK cells promote tumor immune evasion.
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中文摘要
自然杀伤（NK）细胞具有细胞毒及免疫调节功能。本研究鉴定出一类胰岛素样生长因子结合蛋白2（IGFBP2）阳性NK细胞，在肝癌中富集，细胞毒性受损，并与肝癌患者预后不良相关。缺氧肿瘤微环境可诱导NK细胞表达IGFBP2。从机制上看，缺氧促使肿瘤内NK细胞乳酸积累，进而促进IGFBP2启动子区域组蛋白H3赖氨酸18乳酰化（H3K18La），增强IGFBP2转录。NK细胞分泌的IGFBP2抑制邻近肿瘤细胞表达应激相关激活性免疫配体（MICA/B和胞外钙网蛋白[ecto-CRT]），从而降低肿瘤细胞对细胞毒性免疫细胞的敏感性并促进免疫逃逸。抗体介导的IGFBP2阻断可提高肿瘤细胞对细胞毒性免疫细胞的敏感性。此外，在肝癌模型中，IGFBP2阻断与免疫检查点治疗协同，增强抗肿瘤疗效。
展开英文摘要原文
Natural killer (NK) cells are known for their cytotoxic and regulatory functions in immune responses.
Here, we identify a subset of insulin-like growth factor binding protein 2 (IGFBP2) + NK cells enriched in liver cancer, exhibiting impaired cytotoxicity and correlating with poor prognosis in patients with liver cancer. The hypoxic tumor microenvironment induces IGFBP2 expression in NK cells.
Mechanistically, hypoxia drives lactate accumulation in intratumoral NK cells, promoting histone H3 lysine 18 lactylation (H3K18La) at the IGFBP2 promoter and enhancing IGFBP2 transcription. NK cell-secreted IGFBP2 inhibits the expression of stress-related activating immune ligands (MICA/B and ecto-CRT) on neighboring tumor cells, thereby reducing their sensitivity to cytotoxic immune cells and promoting immune evasion. Antibody-mediated IGFBP2 blockade increases tumor cell sensitivity to cytotoxic immune cells.
Additionally, IGFBP2 blockade synergizes with immune checkpoint therapy to enhance anti-tumor efficacy in liver cancer models.
论文信息
- 作者
- Wang X、Hou Z、Sun Q、Cui Q、Shi G、Du X、Liu J、Nian Z
- 第一作者单位
- State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230027, China.China
- 通讯作者单位
- State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230027, China; Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. Electronic address: ustczxh@ustc.edu.cn.China
- 期刊
- Cell reports2026 Jul 28
- 原文标识
- PubMed 42348418 · DOI 10.1016/j.celrep.2026.117612