{"doi":"10.1172/jci193162","title":"USP22 drives tumor immune evasion and checkpoint blockade resistance through EZH2-mediated epigenetic silencing of MHC-I","abstract":"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-mediated neoantigen presentation to CD8+ T cells. Both genetic and pharmacologic USP22 inhibition increased immunogenicity and overcame anti-PD-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 Usp22 inhibition resulted in increased tumoral MHC-I expression and consequently enhanced CD8+ T cell killing, which was largely abrogated by Ezh2 reconstitution. Multiplexed immunofluorescence staining detected a strong reverse correlation between USP22 expression and both β2M expression and CD8+ 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.","journal":"Journal of Clinical Investigation","year":2025,"id":514098,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":409061,"name":"Radhika Iyer","orcid":"0000-0003-1287-3995","position":1,"is_corresponding":false},{"id":1376044,"name":"Yi Li","orcid":"0000-0001-9717-1719","position":2,"is_corresponding":false},{"id":1376045,"name":"Jun Zhu","orcid":"0000-0003-1824-7610","position":3,"is_corresponding":false},{"id":1376675,"name":"Zhaomeng Cai","orcid":null,"position":4,"is_corresponding":false},{"id":646485,"name":"Juncheng Wei","orcid":"0000-0001-5262-477X","position":5,"is_corresponding":false},{"id":1376046,"name":"Cheng Yang","orcid":"0000-0001-7078-3838","position":6,"is_corresponding":false},{"id":477447,"name":"Amy Y. Tang","orcid":"0000-0003-4429-7152","position":7,"is_corresponding":false},{"id":267160,"name":"Hai Wang","orcid":"0000-0002-6999-554X","position":8,"is_corresponding":false},{"id":1253476,"name":"Qiong Gao","orcid":"0009-0002-8416-6026","position":9,"is_corresponding":false},{"id":646489,"name":"Nikita Mani","orcid":"0000-0003-4688-7770","position":10,"is_corresponding":false},{"id":1376676,"name":"Noah Marx","orcid":null,"position":11,"is_corresponding":false},{"id":499189,"name":"Beixue Gao","orcid":"0000-0002-4667-7995","position":12,"is_corresponding":false},{"id":900730,"name":"D. Martin Watterson","orcid":"0000-0001-7605-5866","position":13,"is_corresponding":false},{"id":286164,"name":"Seema A. Khan","orcid":"0000-0002-6307-2023","position":14,"is_corresponding":false},{"id":311672,"name":"William J. Gradishar","orcid":"0000-0002-2772-3140","position":15,"is_corresponding":false},{"id":297924,"name":"Huiping Liu","orcid":"0000-0003-4822-7995","position":16,"is_corresponding":false},{"id":240965,"name":"Deyu Fang","orcid":"0000-0002-4211-2751","position":17,"is_corresponding":false},{"id":1164572,"name":"Kun Liu","orcid":"0009-0000-3274-9989","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:48:23.284782Z","pmid":"41252204","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}