All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer PMID: 42115161

Target-related Cytokines

2026-09-23

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.

Ching-Fei Li ¹ ² , Yongkun Wei ³ , Heng-Huan Lee ³ ⁴ , Wei-Chao Chang ⁵ , Yun Xiong ⁶ , Yitao Tang ⁷ , Riyao Yang ³ ⁸ , Jun Yao ³ , Huamin Wang ⁹ , Xiaofei Wang ¹⁰ , Minghui Liu ³ , Jangho Park ¹⁰ , Jie Fu ³ , Ying-Nai Wang ³ , Li-Yuan Bai ¹¹ , Shao-Chun Wang ⁵ ¹² ¹³ ¹⁴ , Cheng-Wei Chou ³ ¹² ¹⁵ , Jianhua Ling ³ , Yu-Yi Chu ³ , Zhenzhen Xun ⁷ , Han Liang ⁷ , Anirban Maitra ¹⁰ , 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. [email protected].
2. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
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. [email protected].
18. The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].
19. Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
20. Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan. [email protected].
21. Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, and China Medical University, Taichung, Taiwan. [email protected].
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. [email protected].
23. Research Center for Cancer Biology, China Medical University, Taichung, Taiwan. [email protected].

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.