All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer
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.
Authors
- Jangho Park (ORCID: https://orcid.org/0000-0002-6151-5193)
- Ching-Fei Li (ORCID: https://orcid.org/0000-0001-7844-7003)
- Shao‐Chun Wang (ORCID: https://orcid.org/0000-0002-5477-1682)
- Dihua Yu (ORCID: https://orcid.org/0000-0001-6231-9381)
- Zhenzhen Xun (ORCID: https://orcid.org/0009-0007-3667-9771)
- Jianhua Ling (ORCID: https://orcid.org/0000-0002-1315-4389)
- H J Lee
- Ying‐Nai Wang (ORCID: https://orcid.org/0000-0002-5275-6729)
- Paul J. Chiao (ORCID: https://orcid.org/0000-0001-7003-6605)
- Yun Xiong (ORCID: https://orcid.org/0000-0002-8001-129X)
- Yitao Tang (ORCID: https://orcid.org/0000-0002-5340-1890)
- Haoqiang Ying (ORCID: https://orcid.org/0000-0003-0616-2310)
- CK Chou
- Minghui Liu (ORCID: https://orcid.org/0000-0002-1803-2452)
- Xiaofei Wang (ORCID: https://orcid.org/0000-0003-3832-5217)
- Yu‐Yi Chu (ORCID: https://orcid.org/0000-0003-3780-3061)
- Yongkun Wei (ORCID: https://orcid.org/0000-0001-8998-5333)
- Riyao Yang
- Mien-Chie Hung (ORCID: https://orcid.org/0000-0003-4317-4740)
- Wei-Chao Chang
- Jun Yao
- Han Liang (ORCID: https://orcid.org/0000-0001-7633-286X)
- Li-Yuan Bai
- Wantong Yao (ORCID: https://orcid.org/0000-0002-0172-7530)
- Huamin Wang (ORCID: https://orcid.org/0000-0002-2038-5863)
- Anirban Maitra (ORCID: https://orcid.org/0000-0001-7923-9978)
- Jie Fu (ORCID: https://orcid.org/0000-0003-1794-1360)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Asia University (TW)
- China Medical University (TW)
- Taichung Veterans General Hospital (TW)
- Arcadia (US)
- China Medical University Hospital (TW)
- Anderson University - South Carolina (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-11
- DOI
- https://doi.org/10.1038/s41467-026-72271-5
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00