Hyperbaric Oxygen Therapy in Cancer: Friend, Foe, or Context-Dependent Modulator?

Hyperbaric oxygen therapy (HBOT) increases tissue oxygen availability through the administration of near-pure oxygen under elevated atmospheric pressure. Although HBOT is clinically established for several hypoxia-related conditions and selected radiation-induced tissue injuries, its role in oncology remains controversial. This review evaluates HBOT as a context-dependent modulator of tumor and normal-tissue biology by integrating evidence on hypoxia-inducible factor signaling, redox homeostasis, tumor metabolism, vascular remodeling, immune regulation, extracellular matrix organization, cancer stemness, and treatment sensitivity. Available preclinical and clinical evidence does not support the historical assumption that HBOT universally accelerates tumor growth, recurrence, or metastasis, but current evidence is also insufficient to support HBOT as a broadly applicable standalone anticancer therapy. The strongest clinical evidence concerns late radiation-induced normal-tissue injury, particularly radiation cystitis, whereas evidence for direct antitumor activity or treatment sensitization remains predominantly preclinical and context-dependent. Selected experimental models suggest that transient reoxygenation may attenuate hypoxia-dependent signaling, alter redox and metabolic adaptation, and enhance sensitivity to radiotherapy or systemic anticancer treatment, while other models demonstrate increased proliferation or vascular responses. Future studies should incorporate standardized HBOT protocols, direct or surrogate measurements of tumor oxygenation, mechanistic biomarkers, patient stratification based on measurable tumor characteristics such as baseline hypoxia, redox phenotype, and microenvironmental features, and precise treatment scheduling. HBOT may ultimately be most relevant as a biomarker- and timing-guided pharmacodynamic reoxygenation strategy in tumors in which a transient reoxygenation window can be therapeutically exploited.