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
坐骨神经刺激通过多巴胺信号增强 NK 细胞细胞毒性并协同三阴性乳腺癌免疫治疗
英文原题：Sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling and synergizes immunotherapy in triple-negative breast cancer.
查看英文原题
Sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling and synergizes immunotherapy in triple-negative breast cancer.
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研究概要
本研究弥补了癌症治疗中神经免疫调控理解方面的长期空白，为克服 TNBC 免疫耐受提出了一种有前景的策略。
研究思路结论见上方概要
目的
三阴性乳腺癌（TNBC）已显示出对免疫治疗的耐药性。据报道，刺激坐骨神经中携带 ProkR2 的感觉神经元可通过迷走-肾上腺轴释放儿茶酚胺来调节免疫功能。我们旨在探究坐骨神经刺激对 TNBC 抗肿瘤免疫应答及免疫治疗疗效的影响。
方法
我们在TNBC小鼠模型中实施了携带ProkR2的神经元刺激。采用单细胞RNA测序、流式细胞术和免疫组织化学揭示肿瘤免疫微环境的变化。通过免疫细胞清除和受体抑制剂验证神经刺激调控抗肿瘤免疫的细胞与分子机制。
结果
坐骨神经刺激通过激活肿瘤微环境中的自然杀伤（NK）细胞抑制4T1肿瘤生长。D1样多巴胺受体-cAMP-PKA-CREB信号通路对于神经刺激诱导的NK细胞细胞毒性增强和肿瘤抑制至关重要。神经刺激通过IFN-gamma通路上调肿瘤PD-L1表达。将坐骨神经刺激与anti-PD-1治疗联合使用，相比单独使用任一方法，可获得更优的肿瘤控制效果，并显示出良好的安全性。
展开英文摘要原文
METHODS
We implemented ProkR2-bearing neuron stimulation in a TNBC mouse model. Single-cell RNA sequencing, flow cytometry, and immunohistochemistry were employed to uncover alterations in the tumor immune microenvironment. Immune cell depletion and receptor inhibitors were used to verify the cellular and molecular mechanisms by which neurostimulation regulates anti-tumor immunity.
RESULTS
Sciatic nerve stimulation inhibited 4T1 tumor growth by activating natural killer (NK) cells in the tumor microenvironment. The D1-like dopamine receptor-cAMP-PKA-CREB signaling pathway is essential for enhanced NK cell cytotoxicity and tumor inhibition induced by neurostimulation. Neurostimulation upregulated tumor PD-L1 expression through IFN-gamma pathway. Combining sciatic nerve stimulation with anti-PD-1 therapy resulted in superior tumor control compared to either approach alone and demonstrated good safety.
CONCLUSIONS
This research addresses a long-standing gap in understanding neuro-immune regulation in cancer treatment, presenting a promising strategy for overcoming immunoresistance in TNBC.
论文信息
- 作者
- Li G、Jiang Y、Tong H、Liu J、Jiang Z、Zhao Y、Tan K、Zhang Y
- 第一作者单位
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.China
- 通讯作者单位
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: drmaxuelei@gmail.com.China
- 期刊
- Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy2025 Mar
- 原文标识
- PubMed 39951881 · DOI 10.1016/j.drup.2025.101212