Tumor hypoxia represents a fundamental barrier to effective cancer therapy, driving resistance to chemotherapy, radiotherapy, and immunotherapy while fostering invasion and metastasis. Hyperbaric oxygen therapy (HBOT), by substantially increasing dissolved oxygen in plasma, offers a unique approach to reoxygenate tumors and remodel the tumor microenvironment. Preclinical and clinical studies have revealed that HBOT enhances drug penetration, augments radiation-induced DNA damage, alleviates hypoxia-driven immunosuppression, and synergizes with immune checkpoint blockade. At the mechanistic level, HBOT modulates oxidative stress, ferroptosis, angiogenesis, and cancer stem cell maintenance, thereby counteracting hallmarks of therapeutic resistance. Despite these promising findings, controversies remain regarding its dose-response relationship, long-term safety, and the potential for pro-angiogenic effects under certain conditions. Advances in multi-omics profiling, precision imaging, and adaptive trial designs are expected to define optimal treatment parameters and identify predictive biomarkers. We propose that integrating HBOT into multimodal oncologic regimens could overcome hypoxia-associated resistance and improve patient outcomes. Positioned at the intersection of basic mechanisms and clinical translation, HBOT is poised to reshape strategies for personalized cancer therapy.Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.