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通过mRNA脂质纳米颗粒对量身定制的CAR巨细胞进行腹膜内编程,以促进癌症免疫治疗

Kedan Gu^1,2, Ting Liang¹, Luting Hu¹

¹Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.

Nature communications

|December 24, 2025

概括

新的仿真抗原受体巨细胞 (CAR-Ms) 编程策略显示出治疗腹转移的前景. 具有特定细胞内域的定制CAR-Ms与免疫疗法协同作用,重塑瘤微环境以增强抗癌效应.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
生物技术是生物技术.

背景情况:

固体瘤中的腹转移缺乏有效的治疗方法.
化学抗原受体巨细胞 (CAR-Ms) 提供了一个新的治疗途径.
需要对CAR细胞内域 (ICD) 及其机制进行系统的探索.

研究的目的:

开发和评估针对腹转移的量身定制的CAR-Ms.
研究不同CAR ICDs对巨细胞功能的影响.
阐明CAR-Ms重塑瘤微环境的机制.

主要方法:

使用细胞向的mRNA脂质纳米粒子 (mRNA-LNP) 系统.
在CAR-Ms.中评估了36个CAR格式.
使用单细胞RNA测序 (scRNA-seq) 来分析TME变化.
研究的机制性途径包括NF-κB.

主要成果:

带有CD3ζ TLR4 ICD的CAR-Ms显示出强大的适应性免疫激活.
CAR-Ms与PD-1/L1阻塞疗法有显著的协同作用.
CAR-Ms重新编程了免疫抑制的TME,并增加了原始体耗尽的CD8+T细胞 (Tpex).
通过调节NF-κB通路,CAR-Ms对MHC-I和PD-L1的表达进行了上调.

结论:

定制CAR-Ms的腹腔内编程是可行的.
CAR-Ms增强了抗瘤免疫力,克服了TME抑制.
这种方法扩大了对固体瘤CAR-M治疗机制的理解.

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