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Research ArticleImmunologyOncology
Open Access | 
10.1172/JCI180622
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Zhang, H. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Wang, Z. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Wu, J. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Zheng, Y. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
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Zhao, Q.
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1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by
He, S.
in:
JCI
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1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Jiang, H. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Jiang, C. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Wang, T. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Liu, Y. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Cui, L. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Guo, H. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Yi, J. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Jin, H. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Xie, C. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Li, M. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Li, J. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Wang, X. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Xia, L. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Zhang, X. in: JCI | PubMed | Google Scholar
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
2Guangzhou Institute of Clinical Medicine, Guangzhou First People’s Hospital, Guangzhou, China.
3Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
5VIP region, Sun Yat-sen University Cancer Center, Guangzhou, China.
6MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
7School of Food Science and Technology, Dalian Polytechnic University, Dalian, China.
8Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Address correspondence to: Xiaojun Xia, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. Phone: 86.208.734.3997; Email: xiaxj@sysucc.org.cn
Authorship note: HZ and ZW contributed equally to this work.
Find articles by Xia, X. in: JCI | PubMed | Google Scholar
Authorship note: HZ and ZW contributed equally to this work.
Published January 16, 2025 - More info
Published in Volume 135, Issue 2 on January 16, 2025
AbstractStimulator of interferon genes (STING) agonists have been developed and tested in clinical trials for their antitumor activity. However, the specific cell population(s) responsible for such STING activation–induced antitumor immunity have not been completely understood. In this study, we demonstrated that endothelial STING expression was critical for STING agonist–induced antitumor activity. STING activation in endothelium promoted vessel normalization and CD8+ T cell infiltration — which required type I IFN (IFN-I) signaling— but not IFN-γ or CD4+ T cells. Rather than an upstream adaptor for inducing IFN-I signaling, STING acted downstream of interferon-α/β receptor (IFNAR) in endothelium for the JAK1-STAT signaling activation. Mechanistically, IFN-I stimulation induced JAK1-STING interaction and promoted JAK1 phosphorylation, which involved STING palmitoylation at the Cysteine 91 site but not its C-terminal tail (CTT) domain. Endothelial STING and JAK1 expression was significantly associated with immune cell infiltration in patients with cancer, and STING palmitoylation level correlated positively with CD8+ T cell infiltration around STING-positive blood vessels in tumor tissues from patients with melanoma. In summary, our findings uncover a previously unrecognized function of STING in regulating JAK1/STAT activation downstream of IFN-I stimulation and provide a new insight for future design and clinical application of STING agonists for cancer therapy.
Graphical Abstract
Introduction
The stimulator of interferon genes (STING) protein resides in the ER (1). Upon binding with its natural ligand, cyclic GMP-AMP (cGAMP), which is synthesized by cGAMP synthase (cGAS), STING becomes activated and translocates to the Golgi to recruit and activate TANK-binds kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3), inducing type I IFN (IFN-I) signaling, nuclear factor-κB (NF-κB) activation and inflammation responses (2, 3). The full STING protein structure contains a transmembrane (TM) domain, a CDN binding domain (CBD), and a C-terminal tail domain (CTT) essential for recruiting TBK1 and IRF3 for phosphorylation and activation (4). After activation, STING transfers to the Golgi and undergoes palmitoylation at cysteine 88/91 to facilitate STING clustering formation and signal transduction (5). STING signaling plays a critical role in connecting innate and adaptive immunity, as the robust production of IFN-I enhances CD8+ T cell cross priming by tumor antigens (6, 7). On the other hand, STING has been identified as a driver of chronic inflammation and functional decline during ageing or as a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting Hexokinase 2 (8, 9).
Recently, various STING agonists have been developed for cancer therapy by intratumoral injection or systemic administration (10–13). The STING agonists, such as MIW815 (ADU-S100) and MK-1454, have demonstrated strong antitumor efficacy in preclinical studies but failed to elicit antitumor immune responses or immune infiltration in patients with advanced solid tumors or lymphomas (14, 15). A series of studies reported the synergistic effect of STING agonists with other immunotherapy treatments for inducing strong systemic antitumor immune response (16–18), whereas only minimal antitumor responses were detected in clinical trials (19). A major obstacle for inducing strong antitumor immunity by STING agonists is the tumor microenvironment, which is a complex ecosystem. The tumor microenvironment contains not only tumor cells but also tumor vasculatures, immune cells, fibroblasts, extracellular matrix, and more. (20, 21). STING agonists appear to be capable of activating effective IFN-I signaling in many cell types within the tumor microenvironment, such as endothelial cells, macrophages, DCs, and T cells (22–24). However, the specific cell type(s) responsible for the STING agonist–induced antitumor activity in vivo has remained incompletely understood.
Previous studies have shown that the antitumor immunity induced by intratumoral STING agonists was dependent on host IFN-I signaling and CD8+ T cells (7, 25). Nevertheless, the cellular source of IFN-I in the tumor environment remained controversial. Early studies showed that tumor DNA induced STING activation and IFN-I signaling in DCs, which act as the major cellular source of IFN-β (25, 26). However, another study showed that endothelial cells rather than DCs, were the major source of IFN-β after intratumoral cGAMP injection in a mouse melanoma model (27). Moreover, STING activation in the endothelium was shown to be critical for the normalization of tumor vasculature and T cell infiltration (28, 29), suggesting endothelium as an important target of STING agonists. Furthermore, macrophages seem critical for cGAMP-mediated antitumor immunity, as the antitumor effect was ablated when macrophages were depleted (30), yet another study found a dispensable role of macrophages in STING agonist–induced tumor vasculature normalization and antitumor activity (28). An early study carefully examined the impact of STING signaling magnitude on its antitumor effect and suggested that IFN-I, but not TNF-α, was required for optimal antitumor immune responses mediated by STING agonists (31). However, a recent report showed that tumor-associated myeloid cells secreted TNF-α upon STING activation and induced apoptosis of tumor endothelium to promote tumor immunity (32). Hence, the exact cell type and effector immune molecules responsible for intratumoral STING activation–induced antitumor activity remain unclear.
To define the cell type–specific function of STING in intratumor STING agonist–induced tumor inhibition, we used Cre-flox recombination approach to generate tissue-specific Sting (Tmem173) gene knockout mouse models. Surprisingly, we found that Sting knockout in DCs and macrophages had no effect on antitumor activity, but Sting knockout in endothelial cells drastically abolished the antitumor activity of intratumoral STING agonist. Upon IFN-β stimulation, STING in endothelial cells interacted with JAK1 to facilitate JAK1-STAT1 signal transmission and induction of downstream genes for vasculature normalization. The phosphorylation of JAK1 and the palmitoylation of STING at the C91 site, independent of STING CTT domain, was critical for the JAK1-STING interaction. Thus, our findings identify a previously unrecognized role of STING in regulating JAK1-STAT1 signaling downstream of IFN-β and provide a new critical insight for future design and clinical application of STING agonists for cancer therapy.
ResultsSTING agonist–inhibited tumor growth via IFNAR signaling and CD8+ T cells. Intratumoral administration of STING agonists has been demonstrated with effective antitumor activity on multiple mouse tumor models (33, 34). We first verified that intratumoral administration of either a strong (DMXAA) or mild STING agonist (cGAMP) both significantly inhibited B16 mouse melanoma growth (Figure 1, A and B). Furthermore, those cured mice rejected the rechallenge of B16 tumor cells at a distant site, indicating an antitumor immune memory response after STING agonist treatment (Figure 1C). In line with previous studies, intratumoral mRNA expression levels of STING downstream genes such as Ccl5, Cxcl9, Cxcl10, and Ifn-β were all upregulated in tumors after treatment with cGAMP or DMXAA (
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