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.
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.
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 may promote glioblastoma growth, reduce necrosis, and increase tumor volume. Mechanisms include oxidative stress‑induced genomic instability (elevated ROS causing DNA damage and epigenetic changes) and activation of pro‑survival pathways (such as HIF‑1α, VEGF, and bFGF via nitric oxide signaling, as well as intermittent hypoxia‑reoxygenation effects). The overall impact depends on treatment parameters (pressure, duration, frequency) and tumor context.
Clinical research and future therapeutic strategies: HBOT has an established application for radiation necrosis and postoperative recovery. Its exploratory use combines HBOT with radiochemotherapy, though results are inconsistent and large trials are lacking. Future strategies should optimize protocols (precision, individualization via predictive biomarkers like HIF‑1α, CD133, and timing), and explore novel combinations with immune checkpoint inhibitors, targeted therapies (ROS/HIF/VEGF/NF‑κB inhibitors), and Tumor Treating Fields.
Limitations and conclusions: Current clinical evidence is immature – most studies are small‑scale, non‑randomized, and lack standardized HBOT protocols. HBOT exhibits a dual role in glioblastoma: anti‑tumor effects (radiosensitization, chemosensitization, microenvironment remodeling, cancer stem cell attenuation) versus pro‑tumor risks (survival pathway activation, genomic instability). Future research requires well‑designed multicenter RCTs with standardized regimens, biomarker‑driven stratification, and systematic combination strategies to safely integrate HBOT into comprehensive glioblastoma management.