{"doi":"10.1093/neuonc/noae105","title":"Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy","abstract":"BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME). METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance. RESULTS: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice. CONCLUSIONS: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.","journal":"Neuro-Oncology","year":2024,"id":424205,"datarank":0.6516935102198496,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.181369377830477,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.181369377830477,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":21,"citers_with_citation_signal":12,"citers_with_endowment":12,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9672,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT03152318"]},"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":660354,"name":"Jin Muk Kang","orcid":"0000-0002-7949-9160","position":1,"is_corresponding":false},{"id":683351,"name":"Alexandra Miller","orcid":"0000-0002-1159-177X","position":2,"is_corresponding":false},{"id":1220530,"name":"Grace Nguyen","orcid":"0009-0004-0099-7231","position":3,"is_corresponding":false},{"id":1221120,"name":"Minxin Huang","orcid":null,"position":4,"is_corresponding":false},{"id":1095112,"name":"Ji Seon Shim","orcid":"0000-0001-6655-9614","position":5,"is_corresponding":false},{"id":1095558,"name":"Alberto J Bueso-Perez","orcid":null,"position":6,"is_corresponding":false},{"id":491661,"name":"Sara A. 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Antonio Chiocca","orcid":"0000-0001-5183-1670","position":15,"is_corresponding":false},{"id":277126,"name":"Balveen Kaur","orcid":"0000-0001-7738-0804","position":16,"is_corresponding":false},{"id":13182,"name":"Zhongming Zhao","orcid":"0000-0002-3477-0914","position":17,"is_corresponding":false},{"id":264780,"name":"Tae Jin Lee","orcid":"0000-0002-5245-1140","position":18,"is_corresponding":false},{"id":304532,"name":"Ji Young Yoo","orcid":"0000-0002-6767-1111","position":19,"is_corresponding":false},{"id":1220529,"name":"Min Hye Noh","orcid":"0000-0003-2069-6597","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:58:07.191194Z","pmid":"38853689","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":[]}