ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade

Xiaolan Liu, Xufeng Cen, Ronghai Wu, Ziyan Chen, Yanqi Xie, Fengqi Wang, Bing Shan, Linghui Zeng, Jichun Zhou, Bojian Xie, Yangjun Cai, Jinyan Huang, Yingjiqiong Liang, Youqian Wu, Chao Zhang, Dongrui Wang and Hongguang Xia ()
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Xiaolan Liu: Zhejiang University School of Medicine
Xufeng Cen: Zhejiang University Medical Center
Ronghai Wu: Hangzhou PhecdaMed Co.Ltd
Ziyan Chen: Zhejiang University School of Medicine
Yanqi Xie: Zhejiang University School of Medicine
Fengqi Wang: Zhejiang University School of Medicine
Bing Shan: Chinese Academy of Sciences
Linghui Zeng: Hangzhou City University
Jichun Zhou: Zhejiang University School of Medicine
Bojian Xie: Wenzhou Medical University
Yangjun Cai: Wenzhou Medical University
Jinyan Huang: Zhejiang University School of Medicine
Yingjiqiong Liang: Zhejiang University School of Medicine
Youqian Wu: Zhejiang University School of Medicine
Chao Zhang: Zhejiang University School of Medicine
Dongrui Wang: Zhejiang University Medical Center
Hongguang Xia: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39920-5

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