Restoring Physiological Normoxia as an Adjuvant Strategy to Improve Cancer Treatment Outcomes

Abstract

Hypoxia is a central driver of cancer progression, immune evasion, and resistance to anticancer therapies. While hypoxia has traditionally been considered an intrinsic feature of the tumor microenvironment, growing evidence indicates that chronic intermittent hypoxia-particularly that occurring during sleep-represents a systemic and potentially modifiable contributor to hypoxia-driven oncogenic signaling. Sleep-disordered breathing is the most prevalent cause of nocturnal intermittent hypoxia and induces oxidative stress, inflammation, metabolic reprogramming, and immune dysregulation through mechanisms that overlap with those observed in hypoxic tumors.This narrative review synthesizes current experimental, translational, and clinical evidence supporting the concept that restoration of physiological normoxia, especially during sleep, may attenuate hypoxia-mediated cancer biology and improve responsiveness to standard anticancer therapies. We examine the biological effects of normoxia restoration on hypoxia-inducible signaling, redox homeostasis, tumor metabolism, and antitumor immunity, highlighting its potential role as a host-directed, adjuvant strategy rather than a direct tumor-targeting intervention.We further review sleep and airway-centered therapeutic approaches capable of reducing nocturnal hypoxic burden, including continuous positive airway pressure, mandibular advancement devices, upper airway surgery, myofunctional therapy, and respiratory physiotherapy. Although these interventions are not cancer-specific, their ability to stabilize nocturnal oxygenation positions them as clinically relevant tools within a multidisciplinary framework aimed at hypoxia normalization.Collectively, the evidence suggests that nocturnal normoxia is a biologically meaningful and clinically actionable target. Integrating sleep and airway interventions into cancer care pathways may represent a novel avenue to mitigate hypoxia-driven treatment resistance and enhance therapeutic outcomes. Prospective clinical studies incorporating objective measures of hypoxic burden are warranted to validate this integrative approach.Restoration of physiological normoxia is therefore proposed as a host-directed, adjuvant strategy aimed at mitigating hypoxia-driven oncogenic pathways and improving responsiveness to standard anticancer therapies.