Nature communications · 2026
All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer.
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Li Ching-Fei, Wei Yongkun, Lee Heng-Huan, Chang Wei-Chao, Xiong Yun, Tang Yitao, Yang Riyao, Yao Jun, Wang Huamin, Wang Xiaofei, Liu Minghui, Park Jangho, Fu Jie, Wang Ying-Nai, Bai Li-Yuan, Wang Shao-Chun, Chou Cheng-Wei, Ling Jianhua, Chu Yu-Yi, Xun Zhenzhen, Liang Han, Maitra Anirban, Yao Wantong, Yu Dihua, Chiao Paul J, Ying Haoqiang, Hung Mien-Chie
Аннотация
Adenosine deaminase acting on RNA 1 (ADAR1) contributes to immunotherapy resistance by suppressing interferon signaling. Therapeutic targeting of ADAR1 has not been achieved to date in clinical settings. Here, we discover all-trans retinoic acid (ATRA) promotes ADAR1 protein degradation in cancer. In addition, ATRA induces PD-L1 and combination of ATRA and PD-1 blockade reprograms tumor microenvironments to unleash antitumor immunity, thereby impeding tumor growth. Mechanistically, we identify USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts USP7-ADAR1 interaction and promotes ADAR1 ubiquitination and degradation. ATRA leads to ADAR1 retinoylation, which results in disruption of USP7-ADAR1 complex. Our clinical data shows a positive correlation between USP7 and ADAR1 in various types of cancer. Overall, this study sheds light on control of ADAR1 protein turnover and proposes a mechanism-driven combination therapy using ATRA and PD-1/PD-L1 blockade to convert immunologically "cold" into "hot" tumors, holding potential for clinical translation.