{"doi":"10.1093/neuonc/noaf227","title":"YBX1&YBX3 as novel targets to potentiate immune checkpoint blockade response in gliomas","abstract":"BACKGROUND: Glioblastoma (GBM) exhibits profound resistance to CD8⁺ T cell-mediated killing, yet the tumor-intrinsic mechanisms driving this immune evasion remain poorly defined. Our earlier study revealed Checkpoint Kinase 2 (Chek2) as the driver of CD8+ T cell resistance. This study investigates the immunomodulatory program exerted by the CHK2-YBX1&YBX3 regulatory hub. METHODS: Protein-protein interactions were investigated through immunoprecipitation (IP) followed by mass spectrometry (MS) and phosphoproteomics. Single gene knockout of CHEK2, Y-box-binding protein 1 (YBX1), and Y-box-binding protein 3 (YBX3) were generated in human and mouse glioma cells. Transcriptomic and epigenetic alterations were characterized by bulk RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq). Single-cell RNA sequencing and spatial transcriptomics analysis were performed to evaluate CHK2-YBX1&YBX3 related phenotype in human GBM tumors. In vivo survival studies were conducted to assess the therapeutic potential of CHK2-YBX1&YBX3 degradation and immune checkpoint blockade (ICB). RESULTS: CHK2, YBX1, and YBX3 exhibited reciprocal positive regulation and depletion of any of these genes resulted in derepression of pro-inflammatory gene expression. Pharmacological inhibition with the drug targeting YBX1 led to degradation of the CHK2-YBX1&YBX3 hub accompanied by enhanced antigen presentation and antigen-specific CD8⁺ T cell proliferation. Combination therapy targeting CHK2-YBX1&YBX3 hub and ICB significantly improved survival in preclinical glioma models. CONCLUSIONS: These findings define a novel glioma-intrinsic immunosuppressive program and proposes targeting the CHK2-YBX1&YBX3 hub to potentiate response to ICB in glioma.","journal":"Neuro-Oncology","year":2025,"id":534884,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9644,"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":1418511,"name":"Ningjia Zhou","orcid":null,"position":1,"is_corresponding":false},{"id":1067625,"name":"Li Chen","orcid":"0000-0002-5127-5878","position":2,"is_corresponding":false},{"id":1418017,"name":"Levi van Hijfte","orcid":"0000-0002-1402-6784","position":3,"is_corresponding":false},{"id":1383239,"name":"Rima Tulaiha","orcid":null,"position":4,"is_corresponding":false},{"id":494457,"name":"Vivekanudeep Karri","orcid":"0000-0001-7663-1624","position":5,"is_corresponding":false},{"id":283288,"name":"Yalu Zhou","orcid":null,"position":6,"is_corresponding":false},{"id":1007031,"name":"Karl J. Habashy","orcid":"0000-0003-1210-378X","position":7,"is_corresponding":false},{"id":305721,"name":"Víctor A. Arrieta","orcid":"0000-0003-2738-9741","position":8,"is_corresponding":false},{"id":1084722,"name":"Kwang‐Soo Kim","orcid":"0000-0001-7535-7088","position":9,"is_corresponding":false},{"id":913063,"name":"Joseph Duffy","orcid":"0000-0002-7895-3966","position":10,"is_corresponding":false},{"id":1031976,"name":"Ragini Yeeravalli","orcid":"0000-0002-6422-1529","position":11,"is_corresponding":false},{"id":626612,"name":"Deanna Tiek","orcid":"0000-0002-2881-7691","position":12,"is_corresponding":false},{"id":1418018,"name":"Xiao Song","orcid":"0009-0001-7326-9057","position":13,"is_corresponding":false},{"id":1418019,"name":"Snehasis Mishra","orcid":"0000-0003-1809-6306","position":14,"is_corresponding":false},{"id":225603,"name":"Craig Horbinski","orcid":"0000-0001-8340-9992","position":15,"is_corresponding":false},{"id":305714,"name":"Catalina Lee-Chang","orcid":"0000-0002-7675-2124","position":16,"is_corresponding":false},{"id":401411,"name":"Atique U. Ahmed","orcid":"0000-0003-4795-0188","position":17,"is_corresponding":false},{"id":252147,"name":"Lu Wang","orcid":"0000-0002-0073-0666","position":18,"is_corresponding":false},{"id":614270,"name":"Dieter Henrik Heiland","orcid":"0000-0002-9258-3033","position":19,"is_corresponding":false},{"id":271522,"name":"Adam M. Sonabend","orcid":"0000-0002-8347-1945","position":20,"is_corresponding":false},{"id":473633,"name":"Crismita Dmello","orcid":"0000-0002-1688-9663","position":21,"is_corresponding":false},{"id":792808,"name":"Heba Ali","orcid":"0000-0001-5535-7638","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:51:52.019261Z","pmid":"41025501","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":[]}