Glioblastoma, notorious for its aggressive nature and profound resistance to conventional therapies, continues to challenge the realms of neuro-oncology and therapeutic innovation. Among emerging interventions, hyperbaric oxygen therapy (HBOT) has ignited intense scientific debate due to its paradoxical roles in glioblastoma treatment. By drastically elevating oxygen levels within tumor microenvironments, HBOT shows promise in overcoming the hypoxia that fortifies tumor resilience. Yet, this increased oxygen tension simultaneously fuels complex signaling cascades that may spur malignant progression and undermine therapeutic gains.
At its core, glioblastoma is shaped by a profoundly hypoxic niche, where oxygen concentrations plummet, especially within necrotic tumor centers. This oxygen deprivation orchestrates a survival advantage by stabilizing hypoxia-inducible factors (HIFs), which in turn activate resistance genes, stem-like phenotypes, and angiogenic factors. HBOT counteracts this milieu by administering 100% oxygen at pressures exceeding atmospheric levels, substantially augmenting oxygen dissolved in plasma and thereby reversing hypoxia. This elevated pO₂ is hypothesized to re-sensitize glioblastoma to therapies traditionally blunted by the hypoxic barrier.
Crucially, the oxygen-enriched environment generated by HBOT catalyzes a chain reaction of reactive oxygen species (ROS) production. These ROS molecules inflict DNA damage, thereby amplifying the efficacy of radiotherapy by enhancing radiosensitivity. Experimental models have demonstrated that combining HBOT with radiation significantly obstructs tumor proliferation and bolsters apoptosis. Parallel therapeutic benefits extend to chemotherapy, wherein HBOT augments drug cytotoxicity, reduces hypoxia-driven expression of pro-survival mediators such as VEGF and NF-κB, and improves vascular perfusion to facilitate better drug delivery.
Beyond direct cytotoxic potentiation, HBOT profoundly reshapes the tumor microenvironment. Vessel normalization occurs, mitigating abnormal tumor angiogenesis and accompanying peritumoral edema. This vascular recalibration not only ameliorates drug infiltration but also enhances immune cell trafficking, suggesting an immunomodulatory dimension to HBOT. Notably, anti-inflammatory shifts accompany HBOT, characterized by suppressed TNF-α, IL-1β, and NF-κB signaling, and an upregulation of immunoregulatory cytokines like IL-10, potentially recalibrating the immune landscape within the glioblastoma niche.
Importantly, HBOT exerts an inhibitory influence on glioblastoma’s notorious cancer stem cells (CSCs). These CSCs, marked by molecules such as CD133, CD15, and SOX2, underpin therapeutic resistance and relapse through their self-renewal properties. HBOT downregulates these stemness markers and reduces the population of aggressive CD133⁺A2B5⁺ cells, thereby suppressing tumor regeneration capabilities and enhancing long-term treatment outcomes.
Yet, this oxygen-saturation strategy is not without peril. Elevated ROS, while damaging to tumor DNA, concurrently induce oxidative stress–driven genomic instability, potentially accelerating mutational evolution and tumor heterogeneity. This effect could paradoxically heighten malignancy and foster therapeutic evasion. Furthermore, HBOT’s interactions with pro-survival pathways complicate its net impact. Reactive oxygen species serve as upstream activators of nuclear factor-kappa B (NF-κB), promoting inflammatory and survival transcriptional programs. Meanwhile, nitric oxide-mediated signaling during HBOT paradoxically stabilizes HIF-1α, enhancing VEGF and basic fibroblast growth factor (bFGF) expression. This angiogenic surge may potentiate tumor growth and vascular proliferation, sometimes reported in clinical observations of increased tumor volumes following HBOT.
Moreover, the phenomenon of intermittent hypoxia–reoxygenation cycles induced by HBOT imposes additional oxidative stress and further complicates HIF pathway dynamics. The therapeutic outcome on HIF signaling is nuanced, contingent upon specifics such as pressure settings, session duration, treatment frequency, and individual tumor biology, thereby underscoring the challenge of protocol standardization in clinical settings.
Clinically, HBOT has attained established utility for treating radiation necrosis and facilitating postoperative recovery. In such scenarios, HBOT substantially reduces cerebral edema, repairs necrotic tissues, and ameliorates neurologic deficits. Exploratory applications augmenting traditional radiochemotherapy protocols have shown tentative promise in small-scale trials, with some demonstrating prolonged progression-free and overall survival. Nonetheless, these studies lack the methodological robustness and size required for broad clinical endorsement, often neglecting patient stratification and combinatorial innovations.
Looking forward, precision medicine paradigms beckon in HBOT optimization. Detailed evaluation of how variables—including atmospheric pressure, oxygen exposure duration, and dosing frequency—interact with glioblastoma molecular subtypes (such as IDH mutation status and MGMT methylation) could pave the way for individualized treatment regimens. Biomarkers predictive of HBOT responsiveness, such as HIF-1α expression and stemness markers, could further refine patient selection, maximizing benefit while minimizing risk.
In parallel, frontline research is exploring synergy between HBOT and cutting-edge therapies. Immune checkpoint inhibitors, for example, may capitalize on HBOT’s ability to reverse hypoxia-induced immunosuppression, thereby invigorating T-cell–mediated antitumor immunity. Additionally, co-administration with molecular inhibitors targeting ROS, HIF, VEGF, or NF-κB pathways—including agents such as N-acetylcysteine—offers a mechanistic counterbalance to HBOT’s pro-tumorigenic signals. The integration of HBOT with non-conventional modalities like Tumor Treating Fields (TTFields) also warrants investigation to elucidate potential therapeutic amplification.
Despite these advances, the evidence base for HBOT in glioblastoma remains preliminary and heterogeneous. Most clinical studies are small-scale, non-randomized, and utilize non-standardized treatment parameters, fostering inconsistent outcomes and limiting reproducibility. The absence of comprehensive randomized controlled trials and robust biomarker-driven patient stratification constrains clinical translation. Future investigations must adopt multicenter designs with rigorous protocol standardization to unveil the full therapeutic potential and clarify safety parameters.
In essence, HBOT embodies a biochemical double-edged sword in glioblastoma management. Its capacity to dramatically oxygenate hypoxic tumor niches opens avenues to sensitize tumors and modulate hostile microenvironments. Conversely, its propensity to stimulate oxidative stress and pro-survival pathways necessitates careful therapeutic calibration. The promise of HBOT lies in precise, individualized application, synergistic combination therapies, and thorough mechanistic understanding—endeavors that will transform this ancient modality into a sophisticated weapon against one of neuro-oncology’s most formidable foes.
Subject of Research: Hyperbaric Oxygen Therapy in Glioblastoma Treatment
Article Title: Dual Effects and Clinical Application Prospects of Hyperbaric Oxygen Therapy in Glioblastoma: A Mini Review
News Publication Date: 28-Mar-2026
Web References: http://dx.doi.org/10.14218/NSSS.2025.00047
Image Credits: Pan Wang, Nan Wu
Keywords: Glioblastoma, Hyperbaric Oxygen Therapy, Radiosensitization, Chemosensitization, Reactive Oxygen Species, Tumor Microenvironment, Cancer Stem Cells, Hypoxia, HIF-1α, NF-κB, Angiogenesis, Immunotherapy
