全反式维甲酸通过维甲酰化介导的USP7解离使ADAR1蛋白不稳定并改善胰腺癌的免疫治疗
All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer.
摘要(中文译文)
作用于RNA的腺苷脱氨酶1（ADAR1）通过抑制干扰素信号传导促进免疫治疗耐药。迄今为止，在临床环境中尚未实现对ADAR1的治疗性靶向。在此，我们发现全反式维甲酸（ATRA）可促进肿瘤中ADAR1蛋白的降解。此外，ATRA可诱导PD-L1表达，ATRA与PD-1阻断联合治疗可重塑肿瘤微环境，释放抗肿瘤免疫，从而抑制肿瘤生长。在机制上，我们鉴定出USP7是ADAR1蛋白稳定性的关键调控因子。ATRA破坏USP7与ADAR1的相互作用，促进ADAR1的泛素化与降解。ATRA导致ADAR1发生视黄酰化修饰，进而破坏USP7-ADAR1复合物。我们的临床数据显示，在多种类型的癌症中USP7与ADAR1呈正相关。总体而言，本研究揭示了ADAR1蛋白周转的调控机制，并提出了一种机制驱动的联合治疗策略——利用ATRA与PD-1/PD-L1阻断联合，将免疫学上的“冷”肿瘤转化为“热”肿瘤，具有临床转化潜力。
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.
如何引用
AMA
Ching-Fei Li, Yongkun Wei, Heng-Huan Lee, Wei-Chao Chang, Yun Xiong, Yitao Tang, et al. All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer.. Nature communications. 2026; doi:10.1038/s41467-026-72271-5.
APA
Ching-Fei Li, Yongkun Wei, Heng-Huan Lee, Wei-Chao Chang, Yun Xiong, Yitao Tang, et al (2026). All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer.. Nature communications. https://doi.org/10.1038/s41467-026-72271-5
GB/T 7714
Ching-Fei Li, Yongkun Wei, Heng-Huan Lee, Wei-Chao Chang, Yun Xiong, Yitao Tang, et al. All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer.[J]. Nature communications, 2026 doi:10.1038/s41467-026-72271-5.
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