Academic Journal
ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade
| العنوان: | ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade |
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| المؤلفون: | Liu, Xiaolan, Cen, Xufeng, Wu, Ronghai, Chen, Ziyan, Xie, Yanqi, Wang, Fengqi, Shan, Bing, Zeng, Linghui, Zhou, Jichun, Xie, Bojian, Cai, Yangjun, Huang, Jinyan, Liang, Yingjiqiong, Wu, Youqian, Zhang, Chao, Wang, Dongrui, Xia, Hongguang |
| المصدر: | Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| الوصف: | Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-023-39920-5 |
| الاتاحة: | http://dx.doi.org/10.1038/s41467-023-39920-5 https://www.nature.com/articles/s41467-023-39920-5.pdf https://www.nature.com/articles/s41467-023-39920-5 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.4F1877F1 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-023-39920-5 |
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