Immunogenic cell death (ICD) induces an active immune response. Activating ICD represents a potential approach to boost the anti-tumor activity of immunotherapy, highlighting the need to identify effective and safe ICD inducers. In this study, we identified a conserved, ICD-related circular RNA cEMSY by systematically screening ICD models induced by multiple cell stressors in lung adenocarcinoma (LUAD). cEMSY triggered ICD in LUAD both in vitro and in vivo, leading to the release of damage-associated molecular patterns and promoting T cell cross-priming by dendritic cells (DCs). Notably, the intratumoral delivery of lipid nanoparticle-encapsulated cEMSY induced a potent antitumor immune response in an immunosuppressed tumor model, which synergized with PD-1 blockade to facilitate long-term anti-tumor immunity with no apparent toxicities. Mechanistically, cEMSY mediated mitochondrial aggregation of the RNA-binding protein TDP-43 that enabled leakage of mitochondrial DNA to stimulate the cGAS–STING pathway, activating the antiviral immune response. Clinically, elevated expression of cEMSY correlated with enhanced infiltration of DCs and CD8+ T cells and favorable immunotherapy response in LUAD. Together, these findings support the dual potential of cEMSY as a target and biomarker for improving immune checkpoint inhibitor responses in LUAD.

中文翻译：

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circRNA cEMSY 诱导肺腺癌免疫原性细胞死亡并提高免疫治疗效果


免疫原性细胞死亡 （ICD） 诱导主动免疫反应。激活 ICD 代表了一种提高免疫疗法抗肿瘤活性的潜在方法，突出了确定有效和安全的 ICD 诱导剂的必要性。在这项研究中，我们通过系统筛选肺腺癌 （LUAD） 中多个细胞应激源诱导的 ICD 模型，鉴定了一种保守的、与 ICD 相关的环状 RNA cEMSY。cEMSY 在体外和体内 LUAD 中触发 ICD，导致损伤相关分子模式的释放并促进树突状细胞 （DC） 的 T 细胞交叉引发。值得注意的是，脂质纳米颗粒包封的 cEMSY 的瘤内递送在免疫抑制肿瘤模型中诱导了有效的抗肿瘤免疫反应，这与 PD-1 阻断协同作用，促进长期抗肿瘤免疫，无明显毒性。从机制上讲，cEMSY 介导了 RNA 结合蛋白 TDP-43 的线粒体聚集，使线粒体 DNA 泄漏能够刺激 cGAS-STING 通路，激活抗病毒免疫反应。临床上，cEMSY 表达升高与 DC 和 CD8+ T 细胞浸润增强以及 LUAD 中良好的免疫治疗反应相关。总之，这些发现支持 cEMSY 作为改善 LUAD 免疫检查点抑制剂反应的靶标和生物标志物的双重潜力。