{"doi":"10.1007/s11307-025-02037-w","title":"Metabolic Shift Mirrors GBM Immunity to Anti-PD-L1 Immunotherapy: A Deuterium MRS Study","abstract":"Abstract Background/Objectives Immune checkpoint blockade (ICB) therapy has been ineffective in glioblastoma (GBM) that recurs following standard-of-care resection and chemoradiation of the primary tumor. Herein, we investigate whether the delayed effect of intracranial radiation alters the tumor lesion metabolic profile. Methods Naïve (non-irradiated) GL261 tumor cells were implanted into the brains of C57BL/6 mice. Brains of one cohort were hemispherically irradiated six weeks prior to implantation, ultimately resulting in ICB refractory GBM. Brains of the control cohort were not irradiated. Following subcutaneous infusion of [6,6- 2 H 2 ] glucose (Glc), single voxel deuterium metabolic imaging (DMI) monitored Glc uptake and the production of semi-heavy water (HOD), 2 H 2 -lactate (Lac) and the 50/50 mix of [ 2 H 2 -glutamate + 2 H 2 -glutamine] (Glx). Results GL261 tumors growing in previously irradiated brain showed reduced Warburg effect (aerobic glycolysis; glucose → lactate) and greater TCA cycle activity (respiration, oxidative phosphorylation) relative to tumors growing in non-irradiated brain as evidenced by cohort differences in the ratios Glx/Lac (p < 0.01), Glx/Glc (p < 0.02), and Lac/Glc (p < 0.01). Conclusions A metabolic program skewed toward oxidative phosphorylation and away from glycolysis has been associated with immune dysfunction. This study documents such a skewed metabolic state in ICB refractory GL261 GBM growing in irradiated brain (tumors were not irradiated) compared to control brain.","journal":"Molecular Imaging and Biology","year":2025,"id":576752,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9201,"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":559862,"name":"Xia Ge","orcid":null,"position":1,"is_corresponding":false},{"id":297957,"name":"Tanner M. Johanns","orcid":"0000-0003-1094-1528","position":2,"is_corresponding":false},{"id":403243,"name":"John A. Engelbach","orcid":null,"position":3,"is_corresponding":false},{"id":449915,"name":"Keith M. Rich","orcid":"0000-0001-5593-5098","position":4,"is_corresponding":false},{"id":760778,"name":"Joseph J. H. Ackerman","orcid":"0000-0002-6514-9282","position":5,"is_corresponding":false},{"id":323929,"name":"Joel R. Garbow","orcid":"0000-0002-0654-2703","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:58:00.620755Z","pmid":"41044469","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":[]}