SIRT2-mediated deacetylation activates USP22 catalytic function for PD-L1 protein stabilization and tumor immune escape

Na Li; Qiong Gao; Huijun Jia; Guoqing Xue; Yuanzhang Zhou; Shengnan Wang; Suxian Ma; Bingjin Hu; Zhuoyue Zhao; Chen Su; Yinghong Liu; Wenxuan Xi; Zhonghao Li; Donna D. Zhang; Peng Chu; Zhaolin Sun; Deyu Fang

doi:10.1172/JCI198270

¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

⁵Department of Molecular Medicine, Center for Inflammation Science and Systems Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, United States of America

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

Find articles by Li, Z. in: PubMed | Google Scholar

¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

Find articles by Sun, Z. in: PubMed | Google Scholar

¹Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China

²Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

³Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China

⁴Dalian College of Pharmacy, Dalian Medical University, Dalian, China

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J Clin Invest. https://doi.org/10.1172/JCI198270.
Copyright © 2026, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 2, 2026 - Version history

Immune checkpoint blockade (ICB), including PD-1/PD-L1 inhibitors, has transformed cancer therapy but benefits only a subset of patients. Understanding how PD-L1 is regulated and identifying strategies to overcome resistance remain critical. Here, we identify SIRT2 as a key positive regulator of PD-L1 across multiple human cancers. Unexpectedly, SIRT2 does not act at the transcriptional level but stabilizes PD-L1 protein by preventing ubiquitin-mediated degradation. Mechanistically, SIRT2 maintains the protein stability of USP22, a PD-L1 deubiquitinase. Loss of SIRT2 reduces USP22 levels, whereas ectopic USP22 fully rescues PD-L1 expression and reverses the enhanced antitumor immunity induced by SIRT2 inhibition. We further show that SIRT2 directly deacetylates USP22 at lysines 382 and 505 within its catalytic domain, promoting USP22 deubiquitinase activity and protecting both itself and its substrates from degradation. Our findings reveal a molecular mechanism by which an acetylation–deacetylation switch dynamically regulates deubiquitinase catalytic activity. Therapeutically, SIRT2 inhibition synergizes with PD-1/PD-L1 blockade and USP22 inhibition to enhance antitumor immunity. Consistently, protein but not mRNA levels of SIRT2, USP22, and PD- L1 positively correlate in human bladder cancer and melanoma. Together, these findings define a SIRT2–USP22–PD-L1 axis driving tumor immune evasion and highlight SIRT2 as a promising target to improve ICB efficacy.

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SIRT2-mediated deacetylation activates USP22 catalytic function for PD-L1 protein stabilization and tumor immune escape

Na Li,¹ Qiong Gao,² Huijun Jia,³ Guoqing Xue,³ Yuanzhang Zhou,⁴ Shengnan Wang,² Suxian Ma,⁴ Bingjin Hu,⁴ Zhuoyue Zhao,¹ Chen Su,⁴ Yinghong Liu,¹ Wenxuan Xi,⁴ Zhonghao Li,⁴ Donna D. Zhang,⁵ Peng Chu,⁴ Zhaolin Sun,¹ and Deyu Fang²

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SIRT2-mediated deacetylation activates USP22 catalytic function for PD-L1 protein stabilization and tumor immune escape

Na Li,1 Qiong Gao,2 Huijun Jia,3 Guoqing Xue,3 Yuanzhang Zhou,4 Shengnan Wang,2 Suxian Ma,4 Bingjin Hu,4 Zhuoyue Zhao,1 Chen Su,4 Yinghong Liu,1 Wenxuan Xi,4 Zhonghao Li,4 Donna D. Zhang,5 Peng Chu,4 Zhaolin Sun,1 and Deyu Fang2

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Na Li,¹ Qiong Gao,² Huijun Jia,³ Guoqing Xue,³ Yuanzhang Zhou,⁴ Shengnan Wang,² Suxian Ma,⁴ Bingjin Hu,⁴ Zhuoyue Zhao,¹ Chen Su,⁴ Yinghong Liu,¹ Wenxuan Xi,⁴ Zhonghao Li,⁴ Donna D. Zhang,⁵ Peng Chu,⁴ Zhaolin Sun,¹ and Deyu Fang²