Ching-Fei Li, Yongkun Wei, H J Lee, Wei-Chao Chang, Yun Xiong, Yitao Tang, Riyao Yang, Jun Yao, Huamin Wang, Xiaofei Wang, Minghui Liu, Jangho Park, Jie Fu, Ying‐Nai Wang, Li-Yuan Bai, Shao‐Chun Wang, CK Chou, Jianhua Ling, Yu‐Yi Chu, Zhenzhen Xun, Han Liang, Anirban Maitra, Wantong Yao, Dihua Yu, Paul J. Chiao, Haoqiang Ying, Mien-Chie Hung
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. ADAR1, an RNA-editing enzyme, can contribute to immunotherapy resistance by suppressing interferon signaling. This study shows that all-trans retinoic acid (ATRA) promotes ADAR1 degradation, supporting ATRA combined with PD-L1 blockade as a potential therapeutic strategy.