Metabolic adaptation to hypoxia shapes tumor radioresistance and informs stratified radiotherapy

Tumor hypoxia reduces oxygen fixation of radiation-induced damage and drives metabolic adaptations that influence survival after irradiation. This review examines how glycolysis, lactate transport, pentose phosphate pathway activity, glutamine use, lipid remodeling, one-carbon metabolism, and NAD⁺ salvage shape redox buffering, energy and cofactor availability, nucleotide supply, and stress tolerance. We use metabolic repair competence to describe the pre- and peri-irradiation resource state and DNA damage response–redox coupling to describe post-irradiation resource redistribution. Mechanistic directness is uneven. Selected direct hypoxia–metabolism–radiotherapy evidence is strongest for hypoxia-enhanced PARP-inhibitor radiosensitization; MCT1 instead has direct metabolism–radiotherapy evidence with supportive hypoxia-context data but incomplete hypoxia-specific radiotherapy validation. PFKFB3, glutamine-dependent redox support, lipid-antioxidant pathways, MTHFD2, and ATF4 have direct metabolism–radiotherapy evidence in selected preclinical models but incomplete hypoxia-specific validation. Radiation-induced pentose phosphate pathway activation and NAD⁺ redistribution primarily indicate post-damage metabolic reallocation unless pathway perturbation modifies radiation response. Acute, chronic, and cycling hypoxia further create temporal and spatial heterogeneity that limits static selection markers and universal schedules. Translational maturity is also heterogeneous. Nimorazole has mixed randomized evidence in head and neck cancer. FMISO has reached randomized phase II evaluation for hypoxia-guided dose escalation without establishing a generalizable prescription standard, whereas FAZA remains supported mainly by observational and feasibility studies. Metabolism-directed radiosensitizers remain predominantly preclinical, radiomics remains exploratory, and the proposed post-irradiation metabolic intervention window remains hypothesis-generating rather than established. Overall, the evidence favors function-defined, context-specific, and treatment-timed strategies matched to tumor dependence, hypoxia phenotype, radiation parameters, and normal-tissue recovery rather than universal metabolic radiosensitization.