{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:16:58Z","timestamp":1784279818981,"version":"3.55.0"},"reference-count":70,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":43,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health grants","doi-asserted-by":"crossref","award":["R01DK126908,R01DK120330,R01CA257520,CA232347"],"award-info":[{"award-number":["R01DK126908,R01DK120330,R01CA257520,CA232347"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82073768"],"award-info":[{"award-number":["82073768"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Dalian High-Level Talent Innovation Support Program","award":["2019RD03"],"award-info":[{"award-number":["2019RD03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,15]]},"abstract":"<jats:p>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 did not act at the transcriptional level but stabilized PD-L1 protein by preventing ubiquitin-mediated degradation. Mechanistically, SIRT2 maintained the protein stability of USP22, a PD-L1 deubiquitinase. Loss of SIRT2 reduced USP22 levels, whereas ectopic USP22 fully rescued PD-L1 expression and reversed the enhanced antitumor immunity induced by SIRT2 inhibition. We further show that SIRT2 directly deacetylates USP22 at K382 and K505 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\u2013deacetylation switch dynamically regulates deubiquitinase catalytic activity. Therapeutically, SIRT2 inhibition synergized 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 correlated 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.<\/jats:p>","DOI":"10.1172\/jci198270","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T16:00:16Z","timestamp":1780416016000},"source":"Crossref","is-referenced-by-count":1,"title":["SIRT2-mediated deacetylation activates USP22 catalytic function for PD-L1 protein stabilization and tumor immune escape"],"prefix":"10.1172","volume":"136","author":[{"given":"Na","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijun","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Immunology, College of Basic Medical Science,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Immunology, College of Basic Medical Science,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."},{"name":"Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suxian","family":"Ma","sequence":"additional","affiliation":[{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjin","family":"Hu","sequence":"additional","affiliation":[{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Su","sequence":"additional","affiliation":[{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Xi","sequence":"additional","affiliation":[{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghao","family":"Li","sequence":"additional","affiliation":[{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna D.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Center for Inflammation Science and Systems Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Chu","sequence":"additional","affiliation":[{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaolin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China."},{"name":"Dalian College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4211-2751","authenticated-orcid":true,"given":"Deyu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/medsci8010015"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-020-03440-4"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa8172"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S135157"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0512-0"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0928-4"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)32455-2"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13010131"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21631"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.17598"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/35001622"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-016-0461-5"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12685"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01721"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.487736"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2498"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.09.004"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.5"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000784"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.108629"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.21037\/atm-22-6218"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.10.025"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0348-4"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26278"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2020.01.004"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-022-00398-y"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1892"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-01027-5"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-023-01219-9"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-04356-6"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2020.11.005"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29401-6"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1675"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-024-01805-5"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2025.107668"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05609-2"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0910"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.10.010"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202412109"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.14740\/wjon2547"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01314-w"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.7150\/thno.100667"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217005"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109988"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24321-3"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217196"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090331"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad7118"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.02.008"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.04.005"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201800391"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1172\/JCI164528"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adv0766"},{"issue":"12","key":"B55","first-page":"5564","article-title":"The ubiquitin-specific peptidase 22 is a deubiquitinase of CD73 in breast cancer cells","volume":"12","author":"Gregory","year":"2022","journal-title":"Am J Cancer Res"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2246-4"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-15-6407-9_3"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo4116"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.110592"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217196"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ado1533"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.39"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.03.024"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102410"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1807704115"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.12.015"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.06.015"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/celldisc.2015.28"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-2141-9"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.110592"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/198270\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T18:02:07Z","timestamp":1784052127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/198270"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":70,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,6,2]]},"published-print":{"date-parts":[[2026,7,15]]}},"alternative-id":["10.1172\/JCI198270"],"URL":"https:\/\/doi.org\/10.1172\/jci198270","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"article-number":"e198270"}}