(18)F-FDG PET imaging reveals GW4869's suppression of glioblastoma malignant progression and reversal of TMZ chemoresistance via glucose metabolic phenotype remodeling.

PURPOSE: Glioblastoma (GBM) invariably develops resistance to temozolomide (TMZ), necessitating novel therapeutic strategies. This study demonstrates that inhibiting exosome secretion with GW4869 remodels the glucose metabolic phenotype to suppress malignant behavior and reverse TMZ resistance in GBM. METHODS: TMZ-resistant glioblastoma cells (U87TR) were established via concentration-gradient induction. Metabolic profiling was performed using LC-MS. GW4869’s effects were assessed via functional assays (invasion, migration, colony formation), exosome add-back experiments, and ¹⁸F-FDG PET/CT in xenografts. Glycolytic proteins (GLUT-1/HK2/PKM2) were analyzed by immunofluorescence/western blot. RESULTS: U87TR cells exhibited glycolytic hyperactivation. GW4869 (10 µM) suppressed invasion, migration and colony formation without cytotoxicity. It reversed TMZ resistance by downregulating GLUT-1/HK2/PKM2 and inhibiting glycolysis. Exosomes conferred resistance via metabolic remodeling—blocked by glycolytic inhibitor 2-DG. In vivo, GW4869 reduced tumor ¹⁸F-FDG uptake by 28.0% (P < 0.01), and this reduction strongly correlated with in vitro IC₠₀ reduction. CONCLUSION: GW4869 overcomes TMZ resistance by inhibiting exosome-mediated glycolytic reprogramming. ¹⁸F-FDG PET provides a clinically applicable quantitative tool for monitoring resistance reversal. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07668-9.