Beyond static uptake: rethinking [18F]FMISO PET for quantifying and interpreting tumor hypoxia

Abstract Background Tumor hypoxia is a critical microenvironmental determinant of progression, treatment resistance, and prognosis in solid tumors. Among hypoxia-targeted imaging approaches, [ 18 F]fluoromisonidazole ([ 18 F]FMISO) positron emission tomography (PET) provides a noninvasive imaging readout related to the presence, extent, and spatial distribution of tumor hypoxia. Main body This narrative review delineates the oxygen-dependent bioreductive retention mechanism of [ 18 F]FMISO, conventional delayed static imaging paradigms, commonly used quantitative metrics, and clinical evidence across major solid tumors. Evidence is most mature in head and neck cancer, where [ 18 F]FMISO PET has been investigated for baseline risk stratification, on-treatment response monitoring, and hypoxia-guided radiotherapy planning. In glioma, [ 18 F]FMISO PET shows potential for lesion characterization and prognostic stratification, whereas findings in non-small cell lung cancer and other solid tumors remain heterogeneous and largely exploratory. Importantly, static [ 18 F]FMISO uptake should not be interpreted as a direct measure of tissue oxygenation. Instead, it represents a composite imaging phenotype shaped by tracer delivery, perfusion and diffusion, oxygen-dependent cellular retention, background clearance, tissue composition, and analytical methodology. Quantitative outcomes are affected by acquisition timing, reference region selection, threshold definition, spatial resolution, and partial-volume effects. Accordingly, hypoxic volumes and high-uptake subregions should not be regarded as clearly bounded and spatiotemporally stable therapeutic targets. Future integration of multiparametric magnetic resonance imaging, complementary PET tracers, molecular biomarkers, computational modeling, and artificial intelligence may enhance the biological interpretability of [ 18 F]FMISO signals within a broader microenvironmental context. Conclusion [ 18 F]FMISO PET remains a valuable tool for tumor hypoxia imaging, but its clinical translation requires the establishment of standardized acquisition and quantification frameworks, rigorous prospective validation, and direct evidence of therapeutic benefit from hypoxia-guided interventions.