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
脂质纳米颗粒配制的 DNA 通过干扰素信号通路作为癌症免疫治疗的有效免疫调节剂
英文原题：Lipid nanoparticle-formulated DNA acts as a potent immune modulator for cancer immunotherapy through interferon signaling pathways.
查看英文原题
Lipid nanoparticle-formulated DNA acts as a potent immune modulator for cancer immunotherapy through interferon signaling pathways.
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中文摘要
方法
采用微流控混合器系统制备LNP/pDNA复合物。在制剂后不同时间点测定包封率、粒径和转染能力，以评估理化稳定性。在小鼠肿瘤模型中通过瘤内和肌内给药评估体内抗肿瘤疗效。机制研究包括细胞因子谱分析、肿瘤转录组分析以及免疫细胞清除实验。采用TLR9和干扰素信号通路缺陷小鼠模型以解析信号通路的贡献。
结果
LNP/pDNA制剂在长期储存后仍保持包封率和粒径均一性，并维持有效的基因递送。瘤内和肌内给药均抑制肿瘤生长，其中局部递送显示出更优的疗效。LNP/pDNA激活胞质DNA感知通路并诱导强烈的促炎细胞因子产生。转录组分析揭示了强烈的I型和II型干扰素反应以及免疫效应通路的上调。清除实验证实抗肿瘤效应依赖于CD8⁺ T细胞和NK细胞，而不依赖于中性粒细胞和单核细胞。值得注意的是，治疗疗效在TLR9缺陷小鼠中得以保留，但在同时缺乏I型和II型干扰素信号的小鼠中丧失。
结论
LNP/pDNA 通过激活 IFN 依赖性、TLR9 非依赖性通路，诱导强效抗肿瘤免疫，同时调动固有免疫和适应性免疫应答。这些发现支持 LNP/pDNA 作为一种稳定、有效的癌症免疫治疗平台。
展开英文摘要原文
Rationale: Plasmid DNA (pDNA) delivered by lipid nanoparticles (LNPs) represents a promising strategy for cancer immunotherapy, offering both stability of nucleic acids and efficient intracellular delivery.
This study aimed to evaluate the stability and immunotherapeutic potential of LNP/pDNA formulations and to define the mechanisms underlying their antitumor activity. Methods: LNP/pDNA complexes were prepared by a microfluidic mixer system. Encapsulation efficiency, particle size, and transfection capacity were determined at different time points following formulation to assess physicochemical stability. In vivo antitumor efficacy was evaluated using intratumoral and intramuscular administration in murine tumor models. Mechanistic studies included cytokine profiling, transcriptomic analysis of tumors, and immune cell depletion experiments.
Mouse models deficient in TLR9 and interferon signaling pathways were employed to dissect signaling pathway contributions. Results: LNP/pDNA formulations retained encapsulation efficiency and size uniformity after prolonged storage and maintained effective gene delivery. Both intratumoral and intramuscular administration suppressed tumor growth, with local delivery showing superior efficacy.
LNP/pDNA activated cytosolic DNA-sensing pathways and induced robust proinflammatory cytokine production. Transcriptomic analysis revealed strong type I and II interferon responses and upregulation of immune effector pathways. Depletion studies confirmed that antitumor effects were dependent on CD8⁺ T cells and NK cells but independent of neutrophils and monocytes.
Notably, therapeutic efficacy was preserved in TLR9-deficient mice but lost in mice lacking both type I and II interferon signaling. Conclusions: LNP/pDNA induces potent antitumor immunity through activation of IFN-dependent, TLR9-independent pathways, engaging both innate and adaptive immune responses.
These findings support LNP/pDNA as a stable, effective platform for cancer immunotherapy.
论文信息
- 作者
- Chiang CY、Hsieh MS、Chen MY、Tsai YW、Lin CL、Hsu CW、Yu GY、Huang MH
- 单位
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.Taiwan
- 期刊
- Theranostics2026
- 原文标识
- PubMed 41424839 · DOI 10.7150/thno.121364
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