Lai Ping, Liu Lei, Bancaro Nicolò, Troiani Martina, Calì Bianca, Li Yuxin, Chen Jingjing, Singh Prafull Kumar, Arzola Rydell Alvarez, Attanasio Giuseppe, Pernigoni Nicolò, Pasquini Emiliano, Mosole Simone, Rinaldi Andrea, Sgrignani Jacopo, Qiu Shi, Song Pan, Li Yingrui, Desbats Maria Andrea, Ángel Azucena Rendón, Mestre Ricardo Pereira, Cavalli Andrea, Barile Lucio, de Bono Johann, Alimonti Andrea
Institute 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.
Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland.
Immunity. 2025 Apr 8;58(4):811-825.e7. doi: 10.1016/j.immuni.2025.03.005.
Mitochondrial dysfunction is a hallmark of cellular senescence. Here, we investigated whether senescent cells release mitochondrial (mt)DNA into the extracellular space and its impact on innate immunity. We found that both primary senescent cells and tumor cells undergoing therapy-induced senescence actively released mtDNA into the extracellular environment. mtDNA released by senescent cells was packaged within extracellular vesicles and selectively transferred to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment. Upon uptake, extracellular mtDNA enhanced the immunosuppressive activity of PMN-MDSCs via cGAS-STING-NF-κB signaling, thereby promoting tumor progression. While STING activation directly induced NF-κB signaling, it also activated PKR-like endoplasmic reticulum kinase (PERK), which further amplified NF-κB activity, in PMN-MDSCs. mtDNA release from senescent cells was mediated by voltage-dependent anion channels (VDACs), and pharmacological inhibition of VDAC reduced extracellular mtDNA levels, reversed PMN-MDSC-driven immunosuppression, and enhanced chemotherapy efficacy in prostate cancer mouse models. These findings suggest that targeting mtDNA release could reprogram the immunosuppressive tumor microenvironment, improving therapeutic outcomes for chemotherapy-treated patients.
线粒体功能障碍是细胞衰老的一个标志。在此，我们研究了衰老细胞是否会将线粒体（mt）DNA释放到细胞外空间及其对固有免疫的影响。我们发现，原代衰老细胞和经历治疗诱导衰老的肿瘤细胞都会主动将mtDNA释放到细胞外环境中。衰老细胞释放的mtDNA被包裹在细胞外囊泡中，并选择性地转移到肿瘤微环境中的多形核髓系来源抑制细胞（PMN-MDSCs）。摄取后，细胞外mtDNA通过cGAS-STING-NF-κB信号通路增强了PMN-MDSCs的免疫抑制活性，从而促进肿瘤进展。虽然STING激活直接诱导NF-κB信号通路，但它也激活了PMN-MDSCs中的PKR样内质网激酶（PERK），后者进一步放大了NF-κB活性。衰老细胞释放mtDNA是由电压依赖性阴离子通道（VDACs）介导的，对VDAC的药理学抑制降低了细胞外mtDNA水平，逆转了PMN-MDSC驱动的免疫抑制，并增强了前列腺癌小鼠模型中的化疗疗效。这些发现表明，靶向mtDNA释放可以重新编程免疫抑制性肿瘤微环境，改善化疗患者的治疗效果。
