Sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling and synergizes immunotherapy in triple-negative breast cancer

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates Pub Date : 2025-02-10 DOI:10.1016/j.drup.2025.101212

Guangqi Li , Yuting Jiang , Huan Tong , Jifeng Liu , Zedong Jiang , Yunuo Zhao , Keqin Tan , Yu Zhang , Xiaomeng Yin , Hong Yun , Yuxin He , Hu Liao , Jiangjiang Qin , Xuelei Ma

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引用次数: 0

Abstract

Aims

Triple-negative breast cancer (TNBC) has shown resistance to immunotherapy. Stimulating ProkR2-bearing sensory neurons of the sciatic nerve has been reported to regulate immune function by catecholamine release through the vagal-adrenal axis. We aimed to investigate the impact of sciatic nerve stimulation on anti-tumor immune responses and immunotherapy efficacy in TNBC.

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.

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来源期刊

Drug Resistance Updates 医学-药学

CiteScore

26.20

自引率

11.90%

发文量

审稿时长

29 days

期刊介绍： Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research