All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer

Ching-Fei Li; Yongkun Wei; Heng-Huan 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; Cheng-Wei Chou; Jianhua Ling; Yu-Yi Chu; Zhenzhen Xun; Han Liang; Anirban Maitra; Wantong Yao; Dihua Yu; Paul J Chiao; Haoqiang Ying; Mien-Chie Hung

doi:10.1038/s41467-026-72271-5

All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer

Nat Commun. 2026 May 11. doi: 10.1038/s41467-026-72271-5. Online ahead of print.

Authors

Ching-Fei Li^{1

2}, Yongkun Wei³, Heng-Huan Lee^{3

4}, Wei-Chao Chang⁵, Yun Xiong⁶, Yitao Tang⁷, Riyao Yang^{3

8}, Jun Yao³, Huamin Wang⁹, Xiaofei Wang¹⁰, Minghui Liu³, Jangho Park¹⁰, Jie Fu³, Ying-Nai Wang³, Li-Yuan Bai¹¹, Shao-Chun Wang^{5

12

13

14}, Cheng-Wei Chou^{3

12

15}, Jianhua Ling³, Yu-Yi Chu³, Zhenzhen Xun⁷, Han Liang⁷, Anirban Maitra¹⁰, Wantong Yao^{10

16}, Dihua Yu^{3

16}, Paul J Chiao^{3

16}, Haoqiang Ying^{17

18}, Mien-Chie Hung^{19

20

21

22

23}

Affiliations

¹ Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. cli14@mdanderson.org.
² Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. cli14@mdanderson.org.
³ Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.
⁶ Proteomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ The AHMC Dermatology and Research Center, Arcadia, CA, USA.
⁹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, and China Medical University, Taichung, Taiwan.
¹² Graduate Institute of Biomedical Sciences, College of Medicine, and Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan.
¹³ Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
¹⁴ Department of Biotechnology, Asia University, Taichung, Taiwan.
¹⁵ Division of Hematology/Medical Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
¹⁶ The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
¹⁷ Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. HYing@mdanderson.org.
¹⁸ The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. HYing@mdanderson.org.
¹⁹ Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhung@cmu.edu.tw.
²⁰ Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.
²¹ Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, and China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.
²² Graduate Institute of Biomedical Sciences, College of Medicine, and Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.
²³ Research Center for Cancer Biology, China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.

PMID: 42115161
DOI: 10.1038/s41467-026-72271-5

Abstract

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.