Glioblastoma remains a very difficult malignant tumor with a marked tendency for recurrence. Hypoxic microenvironment is a major cause of treatment resistance. Hyperbaric oxygen therapy (HBOT), which increases tissue oxygen tension and reverses hypoxia, has a “dual effect” in the management of glioblastoma. On the other hand, HBOT increases radiosensitivity through the generation of reactive oxygen species (ROS), enhances the efficacy of chemotherapy by enhancing cytotoxicity and improving vascular perfusion, remodels the tumor microenvironment by normalizing blood vessels and modulating immune cells, and weakens the properties of cancer stem cells. On the other hand, HBOT may also promote tumor progression. Oxidative stress induces genomic instability, while activation of prosurvival pathways through HIF, NF‑κB, and VEGF can promote malignant tumor adaptation and proliferation. Considering these conflicting considerations, the clinical application of HBOT in glioblastoma is still in the exploratory stage. Future studies should focus on optimizing the HBOT protocol and exploring its combination with other therapeutic approaches.
introduction
Glioblastoma is the most common and aggressive primary brain tumor, characterized by diffuse invasion and resistance to conventional treatments (surgery, radiotherapy, temozolomide). The hypoxic microenvironment is an important factor in malignant progression and treatment resistance. HBOT (breathing 100% oxygen at 1.5–3.0 atmospheric pressures absolute) significantly increases the oxygen tension in the tumor and provides a promising approach to address hypoxia. However, HBOT exhibits a complex “dual effect” and may enhance antitumor effects, but also poses the risk of promoting tumor progression. This review assesses the therapeutic potential of HBOT by synthesizing current evidence regarding its molecular mechanisms, clinical applications, and future directions.
Biological basis of HBOT in glioblastoma
Oxygen levels in glioblastoma tissue are generally less than 5% and drop to less than 0.1% in the necrotic core. Hypoxia promotes malignant tumor growth, invasion, and resistance by upregulating stem cell markers (CD133), resistance molecules (MGMT, MRP1, MDR-1), and prosurvival pathways (HIF-1α, HIF-2α). HBOT reverses hypoxia by significantly increasing dissolved oxygen in the plasma. However, its efficacy is inconsistent and its dual nature complicates clinical implementation.
Antitumor potential of HBOT
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radiation sensitization: HBOT increases tumor oxygen levels by 100-115%, promoting radiotherapy-induced ROS-mediated DNA damage. Studies have shown that the combination of HBOT and radiotherapy significantly inhibits proliferation, increases apoptosis, and prolongs survival in glioblastoma models.
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chemical sensitization: HBOT enhances the efficacy of nimustine (ACNU) and temozolomide (TMZ) by increasing tumor pO2 and decreasing HIF-1α, TNF-α, IL-1β, VEGF, and NF-κB. Combining HBOT and TMZ reduces vascular density and Ki67 expression, resulting in smaller tumors and longer survival.
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Sensitization with targeted therapy: Combining HBOT with HIF-1α inhibitors (such as vitexin) or CK2 inhibitors inhibits tumor growth and cell survival.
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Microenvironment and immunity: HBOT normalizes tumor vasculature, reduces peritumoral edema, enhances drug delivery and immune cell infiltration, modulates cytokine release (e.g., increases IL-10), and inhibits inflammatory infiltration by suppressing TNF-α, NF-κB, and IL-1β.
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Attenuation of cancer stem cells: HBOT downregulates stemness markers (CD133, CD15, SOX2), inhibits self-renewal and tumorigenesis, and reduces the proportion of CD133+A2B5 cells.
Potential tumor-inducing risks and controversies
Several studies have reported that HBOT promotes glioblastoma growth, reduces necrosis, and increases tumor volume. Mechanisms include:
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Oxidative stress-induced genomic instability: Elevated ROS can cause DNA damage and epigenetic changes, increase mutation rates, and accelerate tumor evolution.
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Activation of pro-survival pathways: ROS can activate NF‑κB at an early stage. HBOT stabilizes HIF-1α through nitric oxide signaling, increases VEGF and bFGF, and promotes angiogenesis and cell proliferation. HBOT can induce intermittent hypoxia-reoxygenation, which itself strongly induces oxidative stress and activates HIF-1α. The overall effect on the HIF pathway depends on treatment parameters (pressure, duration, frequency) and tumor context.
Clinical research and application scenarios
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Established application: Radiation necrosis (RN) treatment and postoperative recovery – HBOT reduces edema, repairs necrotic tissue, and improves neurological symptoms.
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Exploratory application: Combination of HBOT and radiochemotherapy. Although small studies suggest long progression-free and overall survival, results are inconsistent and large trials are lacking. Most studies used a single set of HBOT parameters without subgrouping patients, and combination therapy was limited to conventional radiotherapy and chemotherapy.
Future treatment strategies
Restrictions
As a mini-review, we do not quantitatively synthesize all available data, which may introduce selection bias. The current clinical evidence base is immature, with most studies being small and nonrandomized, and there is no standardized HBOT protocol. Future research will require well-designed multicenter randomized controlled trials with standardized regimens, biomarker-based patient stratification, and systematic exploration of combination strategies.
conclusion
HBOT plays a dual role in the treatment of glioblastoma. On the antitumor side, it increases radiosensitivity and chemosensitivity, improves the tumor microenvironment, and weakens the properties of cancer stem cells. On the tumor-promoting side, it activates pro-survival signaling pathways, increases oxidative stress-related genomic instability, and can promote tumor progression under certain conditions. Future research should focus on optimizing HBOT protocols, conducting rigorous clinical trials, and exploring synergistic combinations with established and emerging treatments (radiochemotherapy, targeted agents, and immunotherapy) to safely and effectively integrate HBOT into comprehensive glioblastoma management.
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Reference magazines:
Gong, S., Liao, B., Zhao, L., Liu, J., Wu, N., and Wang, P. (2026). Dual effects of hyperbaric oxygen therapy in glioblastoma and prospects for clinical application: a mini-review. Neurosurgical subspecialty. https://doi.org/10.14218/nsss.2025.00047. https://www.xiahepublishing.com/3067-6150/NSSS-2025-00047
