Background:Dexamethasone (DEXA) is the routine therapy for tumor- or treatment-associated edema management in glioblastoma, whereas bevacizumab (BEV) is increasingly used as a steroid-sparing alternative. Although both reduce edema, their broader immunometabolic effects remain ill-defined. Here, we examine how DEXA and BEV differentially affect tumor metabolism and microenvironment in patient samples and experimental models. Methods:We integrated 1H-NMR-based metabolomics of human glioblastoma specimens with mechanistic in vitro studies to compare DEXA and BEV. Microenvironmental modulation by DEXA vs BEV was further investigated in vivo in a syngeneic, immunocompetent orthotopic glioma mouse model by flow cytometry and immunohistochemistry, followed by ex vivo co-culture models. Results:Tumors from DEXA-treated patients (n = 12) vs steroid-naive controls (n = 18) showed nine significantly altered metabolites, including increased lactate, cystathionine, and 2-hydroxybutyrate, indicating a metabolically accelerated, proliferation-associated state. In an immunocompetent orthotopic glioma model, DEXA reduced intratumoral T cell infiltration and induced cytokine conditions favoring regulatory T cells (Tregs) and myeloid recruitment. In contrast, BEV elicited a coordinated immunostimulatory phenotype: it increased chemotactic cytokines in vitro (eg CCL5), decreased intratumoral Tregs (CD4+FOXP3+), enhanced activated, Granzyme B (GzmB) expressing effector T cells (CD4+GzmB+) in vivo, and improved spleenocyte-mediated tumor cell killing ex vivo. Conclusions:Together, DEXA promotes an immunosuppressive, metabolically active tumor microenvironment, whereas BEV supports immune infiltration and activation. These data, combining tissue-derived metabolomics with functional and mechanistic studies in vitro, ex vivo, and in vivo, reveal fundamentally divergent immunometabolic effects of anti-edematous therapies with direct implications in clinical practice, particularly alongside immunotherapy in glioblastoma.
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