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
靶向 NK 细胞 CLEC12B 增强癌症免疫治疗
英文原题：Targeting NK cell CLEC12B enhances cancer immunotherapy.
查看英文原题
Targeting NK cell CLEC12B enhances cancer immunotherapy.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
自然杀伤（NK）细胞是固有免疫效应细胞，但其细胞毒性潜力在免疫抑制性肿瘤微环境中可能受损。识别导致这种功能障碍的分子机制对于癌症免疫治疗的进展至关重要。本研究表明，CLEC12B——一种C型凝集素受体——作为抑制性检查点，限制NK细胞介导的抗肿瘤免疫。肿瘤浸润NK细胞中CLEC12B的高表达与肝细胞癌患者不良临床预后相关。我们鉴定脂蛋白脂肪酶为CLEC12B的功能性配体，触发抑制性信号传导，抑制NK细胞活化。我们开发了一种高亲和力纳米抗体作为潜在治疗手段，可破坏CLEC12B-脂蛋白脂肪酶轴，从而在临床前模型中重振NK细胞活性并抑制肿瘤进展。此外，该纳米抗体与PD-1阻断联合使用时具有强效协同疗效。这些发现确立了CLEC12B作为重新武装免疫系统对抗实体恶性肿瘤的有前景的治疗靶点。
展开英文摘要原文
Natural killer (NK) cells are innate immune effectors, but their cytotoxic potential can be compromised within the immunosuppressive tumor microenvironment. Identifying molecular mechanisms that underly this dysfunction is essential for advances in cancer immunotherapy.
Here we show that CLEC12B, a C-type lectin receptor, functions as an inhibitory checkpoint that restricts NK cell-mediated antitumor immunity. High expression of CLEC12B by tumor-infiltrating NK cells correlates with poor clinical prognosis in patients with hepatocellular carcinoma.
We identify lipoprotein lipase as a functional ligand for CLEC12B, triggering inhibitory signaling that suppresses NK cell activation.
We developed a high-affinity nanobody as a potential therapeutic that disrupts the CLEC12B-lipoprotein lipase axis, thereby revitalizing NK cell activity and suppressing tumor progression in preclinical models.
Furthermore, this nanobody has potent synergistic efficacy when combined with PD-1 blockade.
These findings establish CLEC12B as a promising therapeutic target for rearming the immune system against solid malignancies.
论文信息
- 作者
- Sun P、Xu X、Hu B、Zhang K、Khan A、Chen H、Liu H、Khan S
- 第一作者单位
- Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China.China
- 通讯作者单位
- Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn.China
- 期刊
- Nature immunology2026 May
- 原文标识
- PubMed 41844941 · DOI 10.1038/s41590-026-02471-0