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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • 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

摘要

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.