Impact of corticosteroid administration on glioblastoma progression before and after adjuvant treatments: recent updates on contradictory findings and mechanistic interactions

Corticosteroids, particularly dexamethasone (DEX), are widely used in the supportive management of glioblastoma and grade 4 astrocytoma because of their rapid efficacy in reducing vasogenic cerebral edema and alleviating neurological symptoms. Despite these benefits, their impact on tumor biology and treatment response remains highly controversial. While experimental studies have reported anti-proliferative and anti-migratory effects of DEX in glioma models, accumulating clinical and translational evidence suggests detrimental interactions with radiotherapy (RT) and temozolomide (TMZ), particularly when steroids are administered at higher doses or during RT. Proposed mechanisms include induction of chemoresistance, suppression of antitumor immune responses, and modulation of DNA damage repair pathways within the tumor microenvironment. Recent data implicate steroid receptor coactivator-1 (SRC-1) as a key molecular mediator linking corticosteroid signaling to immune regulation and tumor recurrence, highlighting a novel microenvironmental mechanism independent of steroid dose. Emerging therapeutic strategies, including agents targeting epigenetic regulators, metabolic pathways, or repurposed drugs such as Riluzole, Metformin, Mifepristone, and Chlorpromazine, show promise in mitigating steroid-associated resistance to TMZ. Collectively, these findings emphasize the complex, context-dependent role of corticosteroids in glioblastoma or grade 4 astrocytoma and emphasize the need for optimized dosing, timing, and integrated treatment strategies to improve patient outcomes.