{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:29:10Z","timestamp":1791559750558,"version":"4.3.4"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":45,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01DK126908,R01DK120330,R01CA257520,R01CA284740"],"award-info":[{"award-number":["R01DK126908,R01DK120330,R01CA257520,R01CA284740"]}]},{"name":"NIH","award":["CA232347"],"award-info":[{"award-number":["CA232347"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:p>\n                    While immune checkpoint blockade (ICB) therapy has revolutionized the antitumor therapeutic landscape, it remains successful in only a small subset of patients with cancer. Poor or loss of MHC-I expression has been implicated as a common mechanism of ICB resistance. Yet, the molecular mechanisms underlying impaired MHC-I remain to be fully elucidated. Herein, we identified USP22 as a critical factor responsible for ICB resistance through suppressing MHC-I\u2013mediated neoantigen presentation to CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Both genetic and pharmacologic USP22 inhibition increased immunogenicity and overcame anti\u2013PD-1 immunotherapeutic resistance. At the molecular level, USP22 functions as a deubiquitinase for the methyltransferase EZH2, leading to transcriptional silencing of MHC-I gene expression. Targeted\n                    <jats:italic>Usp22<\/jats:italic>\n                    inhibition resulted in increased tumoral MHC-I expression and consequently enhanced CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell killing, which was largely abrogated by\n                    <jats:italic>Ezh2<\/jats:italic>\n                    reconstitution. Multiplexed immunofluorescence staining detected a strong reverse correlation between USP22 expression and both \u03b22M expression and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocyte infiltration in solid tumors. Importantly, USP22 upregulation was associated with ICB immunotherapeutic resistance in patients with lung cancer. Collectively, this study highlights the role of USP22 as a diagnostic biomarker for ICB resistance and provides a potential therapeutic avenue to overcome the current ICB resistance through inhibition of USP22.\n                  <\/jats:p>","DOI":"10.1172\/jci193162","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T17:00:25Z","timestamp":1763485225000},"source":"Crossref","is-referenced-by-count":15,"title":["USP22 drives tumor immune evasion and checkpoint blockade resistance through EZH2-mediated epigenetic silencing of MHC-I"],"prefix":"10.1172","volume":"136","author":[{"given":"Kun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1287-3995","authenticated-orcid":true,"given":"Radhika","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, 920th Hospital of Joint Logistics Support Force, Kunming, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Oncology, 920th Hospital of Joint Logistics Support Force, Kunming, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaomeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juncheng","family":"Wei","sequence":"additional","affiliation":[{"name":"Center of Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy Y.","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita Lavanya","family":"Mani","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah","family":"Marx","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beixue","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert H. Lurie Comprehensive Cancer Center and Center for Human Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Martin","family":"Watterson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema A.","family":"Khan","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, Robert H. 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