Exposure to ionizing radiation, a physical treatment that inactivates live tumor cells, has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials. However, the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored. Here, we demonstrate that oxidized mitochondrial DNA (mtDNA) and stimulator of interferon genes (STING) signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine. Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells. Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells (DCs). Oxidized mtDNA, as a DAMP or adjuvant, activated the STING-TBK1-IRF3-IFN-β pathway in DCs, which subsequently cross-presented irradiated tumor cell-derived antigens to CD8+ T cells and elicited antitumor immunity. The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity, which may have implications for new strategies to improve the efficacy of irradiated vaccines.

中文翻译：

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通过 STING 信号传导的氧化线粒体 DNA 传感促进了辐照免疫原性癌细胞疫苗的抗肿瘤作用。

电离辐射是一种使活肿瘤细胞失活的物理治疗方法，在动物研究和人体临床试验中已被广泛应用于增强癌细胞疫苗诱导的抗肿瘤反应。然而，辐照细胞作为免疫原性肿瘤疫苗和诱导有效抗肿瘤反应的机制尚未得到充分探索。在这里，我们证明氧化的线粒体 DNA (mtDNA) 和干扰素基因刺激物 (STING) 信号传导在通过辐照肿瘤细胞疫苗实现的增强抗肿瘤作用中起关键作用。可在辐照的肿瘤细胞中诱导 ROS 和氧化的 mtDNA 8-OHG 含量的升高。源自辐照肿瘤细胞的氧化 mtDNA 可以进入树突状细胞 (DC) 的胞质溶胶。氧化的 mtDNA，作为 DAMP 或佐剂，激活 DCs 中的 STING-TBK1-IRF3-IFN-β 通路，随后将辐照的肿瘤细胞衍生抗原交叉呈递给 CD8+ T 细胞并引发抗肿瘤免疫。我们的研究结果提供了对辐照细胞疫苗介导抗肿瘤免疫机制的深入了解，这可能对提高辐照疫苗功效的新策略产生影响。