Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted non-classical functions of Ku70 in cellular processes. However, its function in immune homeostasis and anti-tumor immunity remains unknown. Here, we discovered a marked association between elevated Ku70 expression and unfavorable prognosis in lung adenocarcinoma, focusing specifically on increased Ku70 levels in tumor-infiltrated Treg cells. Using a lung-colonizing tumor model of in mice with Treg-specific Ku70 deficiency, we demonstrated that deletion of Ku70 in Treg cells led to a stronger anti-tumor response and slower tumor growth due to impaired immune-suppressive capacity of Treg cells. Furthermore, we confirmed that Ku70 played a critical role in sustaining the suppressive function of human Treg cells. We found that Ku70 bound to FOXP3 and occupied FOXP3-bound genomic sites to support its transcriptional activities. These findings not only unveil a non-homologous end joining (NHEJ)-independent role of Ku70 crucial for Treg suppressive function, but also underscore the potential of targeting Ku70 as an effective strategy in cancer therapy, aiming to both restrain cancer cells and enhance pulmonary anti-tumor immunity.

中文翻译：

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Ku70 的非经典作用通过肺腺癌的 FOXP3 依赖性机制促进 Treg 抑制功能。


Ku70 是一种 DNA 修复蛋白，与受损的 DNA 末端结合并协调其他蛋白质的募集，以促进 DNA 双链断裂的修复。除了在 DNA 修复中的重要作用外，一些研究还强调了 Ku70 在细胞过程中的非经典功能。然而，它在免疫稳态和抗肿瘤免疫中的功能仍然未知。在这里，我们发现 Ku70 表达升高与肺腺癌不良预后之间存在显着关联，特别关注肿瘤浸润 Treg 细胞中 Ku70 水平的增加。使用 Treg 特异性 Ku70 缺陷小鼠的肺定植肿瘤模型，我们证明由于 Treg 细胞的免疫抑制能力受损，Treg 细胞中 Ku70 的缺失导致更强的抗肿瘤反应和更慢的肿瘤生长。此外，我们证实 Ku70 在维持人 Treg 细胞的抑制功能中起关键作用。我们发现 Ku70 与 FOXP3 结合并占据 FOXP3 结合的基因组位点以支持其转录活性。这些发现不仅揭示了 Ku70 的非同源末端连接 （NHEJ） 非同源末端连接 （NHEJ） 对 Treg 抑制功能至关重要的作用，而且还强调了靶向 Ku70 作为癌症治疗有效策略的潜力，旨在抑制癌细胞和增强肺抗肿瘤免疫力。