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

ABSTRACT: ADAR1-p150 isoform, an interferon-stimulated double-stranded RNA-editing enzyme, contributes to immunotherapy resistance by suppressing interferon signaling. While genetic depletion of ADAR1 overcomes immunotherapy resistance in preclinical models, therapeutic targeting of ADAR1 has not been achieved to date in clinical setting. In this study, we found that the FDA-approved all-trans retinoic acid (ATRA) promoted ADAR1 protein degradation in different types of cancer. In addition, ATRA also induces the transcription of PD-L1 in cancer cells and the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment to unleash antitumor immunity, thereby impeding tumor growth in vivo. Mechanistically, we identified deubiquitinase USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts the USP7-ADAR1 interaction, promoting ADAR1 degradation. Notably, the regulation of ADAR1 protein degradation by ATRA is independent of its canonical receptors. Instead, ATRA treatment leads to ADAR1 retinoylation, a post-translational modification by conjugation of retinoids, which results in the disruption of USP7-ADAR1 complex to promote ADAR1polyubiquitination. Importantly, clinical data shows a positive correlation between USP7 and ADAR1 protein expression in various cancers, supporting USP7's role in ADAR1 stabilization. Overall, this study sheds light on the 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.

INSTRUMENT(S): Orbitrap Ascend

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Yun Xiong  

PROVIDER: MSV000098564 | MassIVE | Sat Jul 19 09:25:00 BST 2025

SECONDARY ACCESSION(S): PXD066324

REPOSITORIES: MassIVE