{"doi":"10.1172/jci.insight.177141","title":"Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment","abstract":"The efficacy of chimeric antigen receptor T cell (CAR-T) therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28 EGFRvIII gliomas revealed impaired mitochondrial ATP production and a markedly hypoxic status compared with ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of the AMPK activator metformin and the mTOR inhibitor rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-γ coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective antiglioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28 EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group, with fewer Ly6c+CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions under in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.","journal":"JCI Insight","year":2024,"id":418691,"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":47,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"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":1207165,"name":"Keith Kyewalabye","orcid":"0000-0003-3645-6328","position":1,"is_corresponding":false},{"id":748177,"name":"Akane Yamamichi","orcid":"0000-0002-8141-7339","position":2,"is_corresponding":false},{"id":615212,"name":"Tiffany Chen","orcid":"0000-0003-2546-2941","position":3,"is_corresponding":false},{"id":685164,"name":"Su Phyu","orcid":"0000-0003-1775-6966","position":4,"is_corresponding":false},{"id":634193,"name":"Pavlina Chuntova","orcid":"0000-0002-5356-9909","position":5,"is_corresponding":false},{"id":271177,"name":"Takahide Nejo","orcid":"0000-0002-9191-8823","position":6,"is_corresponding":false},{"id":561949,"name":"Lauren S. Levine","orcid":"0000-0001-5504-7736","position":7,"is_corresponding":false},{"id":15988,"name":"Matthew H. Spitzer","orcid":"0000-0002-5291-3819","position":8,"is_corresponding":false},{"id":271186,"name":"Hideho Okada","orcid":"0000-0003-0076-9920","position":9,"is_corresponding":false},{"id":748178,"name":"Ryusuke Hatae","orcid":"0000-0001-5636-8064","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T01:57:09.067930Z","pmid":"38386420","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":[]}