Glioblastoma remains a highly challenging malignancy with a pronounced tendency for recurrence. The hypoxic microenvironment is a key contributor to its therapy resistance. Hyperbaric oxygen therapy (HBOT), which elevates tissue oxygen pressure and reverses hypoxia, exhibits a "dual effect" in glioblastoma management. On one hand, HBOT enhances radiosensitivity through reactive oxygen species (ROS) generation, increases chemotherapy efficacy by augmenting cytotoxicity and improving vascular perfusion, remodels the tumor microenvironment via vessel normalization and immune cell modulation, and attenuates cancer stem cell properties. On the other hand, HBOT may also promote tumor progression: oxidative stress can induce genomic instability, while activation of HIF, NF‑κB, and VEGF‑mediated pro‑survival pathways may facilitate malignant adaptation and proliferation. Given these opposing considerations, the clinical application of HBOT in glioblastoma remains exploratory. Future research should focus on optimizing HBOT protocols and exploring combinations with other therapeutic approaches.
Introduction
Glioblastoma is the most common and aggressive primary brain tumor, characterized by diffuse invasion and resistance to conventional therapies (surgery, radiotherapy, temozolomide). The hypoxic microenvironment is a critical driver of malignant progression and treatment resistance. HBOT (breathing 100% oxygen at 1.5–3.0 atmospheres absolute) markedly increases tumor oxygen tension, offering a promising approach to counteract hypoxia. However, HBOT exhibits a complex "dual effect" – it may enhance anti‑tumor efficacy but also poses a risk of promoting tumor progression. This review evaluates the therapeutic potential of HBOT by synthesizing current evidence on its molecular mechanisms, clinical applications, and future directions.
Biological Basis of HBOT in Glioblastoma
Glioblastoma tissues generally have oxygen levels below 5%, dropping below 0.1% in necrotic cores. Hypoxia promotes malignant growth, invasion, and resistance by upregulating stem cell markers (CD133), resistance molecules (MGMT, MRP1, MDR‑1), and pro‑survival pathways (HIF‑1α, HIF‑2α). HBOT reverses hypoxia by greatly increasing oxygen dissolved in plasma. However, its effects are inconsistent, and the dual nature complicates clinical implementation.
Anti‑tumor Potential of HBOT
Radiosensitization: HBOT raises tumor oxygen levels by 100–115%, boosting ROS‑mediated DNA damage from radiotherapy. Studies show that HBOT combined with radiotherapy significantly inhibits proliferation, increases apoptosis, and extends survival in glioblastoma models.
Chemosensitization: HBOT enhances the efficacy of nimustine (ACNU) and temozolomide (TMZ) by increasing tumor pO₂, lowering HIF‑1α, TNF‑α, IL‑1β, VEGF, and NF‑κB. Combining HBOT with TMZ reduces vessel density and Ki67 expression, leading to smaller tumors and longer survival.
Targeted therapy sensitization: HBOT combined with HIF‑1α inhibitors (e.g., vitexin) or CK2 inhibitors suppresses tumor growth and cell survival.
Microenvironment and immunity: HBOT normalizes tumor vessels, reduces peritumoral edema, enhances drug delivery and immune cell infiltration, modulates cytokine release (e.g., increasing IL‑10), and inhibits inflammatory infiltration by suppressing TNF‑α, NF‑κB, and IL‑1β.
Cancer stem cell attenuation: HBOT downregulates stemness markers (CD133, CD15, SOX2), inhibits self‑renewal and tumor formation, and reduces the proportion of CD133⁺A2B5 cells.
Potential Pro‑tumorigenic Risks and Controversies
Several studies report that HBOT promotes glioblastoma growth, reduces necrosis, and increases tumor volume. Mechanisms include:
Oxidative stress‑induced genomic instability: Elevated ROS may cause DNA damage and epigenetic changes, increasing mutation rates and accelerating tumor evolution.
Activation of pro‑survival pathways: ROS can activate NF‑κB early on. HBOT stabilizes HIF‑1α through nitric oxide signaling, increasing VEGF and bFGF, promoting angiogenesis and cell growth. HBOT may 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
Established application: Treatment of radiation necrosis (RN) and postoperative recovery – HBOT reduces edema, repairs necrotic tissue, and improves neurological symptoms.
Exploratory application: Combining HBOT with radiochemotherapy. Small‑scale studies suggest prolonged progression‑free and overall survival, but results are inconsistent and large trials are lacking. Most studies used a single set of HBOT parameters without patient subgrouping, and combination therapies have been limited to traditional radiotherapy and chemotherapy.
Future Therapeutic Strategies
Optimization of treatment protocols:
Precision – Study biological effects of different HBOT parameters (pressure, duration, frequency) across glioblastoma molecular subtypes (IDH mutation, MGMT methylation, stem cell markers).
Individualization – Identify predictive biomarkers (HIF‑1α, CA9, CD133, CD15, SOX2) to select patients most likely to benefit.
Timing – Determine optimal temporal combination with radiotherapy and chemotherapy (before, during, or after).
Exploration of novel combination strategies:
Immune checkpoint inhibitors – HBOT may reverse hypoxia‑mediated immunosuppression, enhancing T‑cell activity and overcoming resistance.
Targeted therapy – Combine HBOT with inhibitors of ROS, HIF, VEGF, or NF‑κB pathways (e.g., N‑acetylcysteine).
Tumor Treating Fields (TTFields) – Explore whether HBOT affects TTFields efficacy.
Limitations
As a mini‑review, it does not quantitatively synthesize all available data, which may introduce selection bias. The current clinical evidence base is immature – most studies are small‑scale, non‑randomized, and lack standardized HBOT protocols. Future research requires well‑designed multicenter randomized controlled trials with standardized regimens, biomarker‑driven patient stratification, and systematic exploration of combinatorial strategies.
Conclusions
HBOT exhibits a dual role in glioblastoma treatment. On the anti‑tumor side, it enhances radiosensitivity and chemosensitivity, improves the tumor microenvironment, and attenuates cancer stem cell properties. On the pro‑tumor side, it may activate pro‑survival signaling pathways, increase oxidative stress‑related genomic instability, and potentially facilitate 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 therapies (radiochemotherapy, targeted agents, immunotherapy) to safely and effectively integrate HBOT into comprehensive glioblastoma management.
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The study was recently published in the Neurosurgical Subspecialties .
Neurosurgical Subspecialties (NSSS) is the official scientific journal of the Department of Neurosurgery at Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. NSSS aims to provide a forum for clinicians and scientists in the field, dedicated to publishing high-quality and peer-reviewed original research, reviews, opinions, commentaries, case reports, and letters across all neurosurgical subspecialties. These include but are not limited to traumatic brain injury, spinal and spinal cord neurosurgery, cerebrovascular disease, stereotactic radiosurgery, neuro-oncology, neurocritical care, neurosurgical nursing, neuroendoscopy, pediatric neurosurgery, peripheral neuropathy, and functional neurosurgery.
