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J Clin Invest. 2018 Mar 1;128(3):1057-1073. doi: 10.1172/JCI96329. Epub 2018 Feb 12.

STAT3/p53 pathway activation disrupts IFN-β-induced dormancy in tumor-repopulating cells.

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National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, and.
Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, China.
Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China.
Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, and.
Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, and Suzhou Institute of Systems Medicine, Suzhou, China.


Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.


Cancer; Immunology; Melanoma; Signal transduction; Stem cells

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