{"doi":"10.7554/elife.94849.2","title":"Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway","abstract":"Abstract The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt−/−) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt−/− cancer cells restored tumor growth, and this correlated with impaired CD8+ T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.","journal":"eLife","year":2024,"id":491728,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":902026,"name":"Bao Zhao","orcid":"0000-0003-3599-1230","position":1,"is_corresponding":false},{"id":861922,"name":"Hong Dong","orcid":"0000-0001-6719-4880","position":2,"is_corresponding":false},{"id":693755,"name":"Tianliang Li","orcid":"0000-0003-2673-0549","position":3,"is_corresponding":false},{"id":232143,"name":"Xiang Cheng","orcid":"0000-0001-5315-9830","position":4,"is_corresponding":false},{"id":663381,"name":"Wang Gong","orcid":"0000-0002-2116-3453","position":5,"is_corresponding":false},{"id":1170784,"name":"Jing Wang","orcid":"0000-0002-4122-5471","position":6,"is_corresponding":false},{"id":356390,"name":"Junran Zhang","orcid":"0000-0001-5413-3675","position":7,"is_corresponding":false},{"id":78715,"name":"Gang Xin","orcid":null,"position":8,"is_corresponding":false},{"id":11782,"name":"Yanbao Yu","orcid":"0000-0003-2994-1974","position":9,"is_corresponding":false},{"id":109672,"name":"Yu L. Lei","orcid":"0000-0002-9868-9824","position":10,"is_corresponding":false},{"id":333403,"name":"Jennifer D. Black","orcid":"0000-0001-8813-6604","position":11,"is_corresponding":false},{"id":270306,"name":"Zihai Li","orcid":"0000-0003-4603-927X","position":12,"is_corresponding":false},{"id":515128,"name":"Haitao Wen","orcid":"0000-0002-6363-2748","position":13,"is_corresponding":false},{"id":892822,"name":"Jianwen Chen","orcid":"0000-0002-4438-7898","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:08:45.247225Z","pmid":null,"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":[]}