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由衰老的瘤细胞释放的线粒体DNA通过cGAS-STING通路增强PMN-MDSC驱动的免疫抑制

Ping Lai¹, Lei Liu², Nicolò Bancaro²

¹Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne 1011, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland.

|April 9, 2025

概括

衰老细胞释放包装在囊泡中的线粒体DNA (mtDNA),从而增强瘤中的免疫抑制性髓状细胞. 通过VDAC通道抑制mtDNA释放改善了前列腺癌模型中的化疗疗效率.

科学领域:

免疫学免疫学免疫学
细胞生物学细胞生物学
癌症研究癌症研究

背景情况:

细胞衰老与线粒体功能障碍有关.
细胞外线粒体DNA (mtDNA) 在先天免疫和瘤进展中的作用尚未完全理解.

研究的目的:

为了研究老化细胞中mtDNA的释放.
确定细胞外mtDNA对瘤微环境和先天免疫的影响.
探索针对mtDNA释放的治疗潜力.

主要方法:

分析了初级和治疗诱导的衰老细胞的mtDNA释放.
描述了含有mtDNA的细胞外囊泡.
研究了mtDNA转移到多态核核髓衍生抑制细胞 (PMN-MDSCs) 的过程.
研究了cGAS-STING-NF-κB和PERK的信号通路.
在前列腺癌小鼠模型中,依赖电压的离子通道 (VDAC) 在药理上是目标.

主要成果:

衰老细胞积极释放mtDNA到细胞外环境中,包装在细胞外囊泡中.
细胞外mtDNA转移到PMN-MDSCs,通过cGAS-STING-NF-κB和PERK信号传递增强其免疫抑制活性.
在临床前模型中,VDAC的药理抑制减少了细胞外mtDNA,逆转了PMN-MDSC免疫抑制,并改善了化疗疗效.

结论:

由衰老细胞释放的细胞外mtDNA通过增强PMN-MDSC免疫抑制促进瘤进展.
针对VDAC介导的mtDNA释放提供了一个潜在的策略来重编程瘤微环境.
抑制mtDNA释放可能会改善接受化疗的癌症患者的治疗结果.

关键词:

垃圾填埋场是一个垃圾填埋场.这就是PMN-MDSCs.在cGAS-STING路径中.免疫抑制是一种免疫抑制.这是先天的免疫力.我们的mtDNA mtDNA 衰老是一种老化.瘤微环境是一个微环境.

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