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GSH depletion will lower a cell's capacity to buffer against endogenous oxidants, and it may set a time limit on continued mitochondrial function and thus indirectly on total ATP levels and membrane integrity

3.1 Complexity and heterogeneity of DTP cell states A major challenge lies in the inherent complexity and heterogeneity of DTP cells, both within and between tumor populations ( 3.2 Lack of robust and specific biomarkers Another major impediment is the absence of well-defined biomarkers capable of accurately identifying and tracking DTP cells in clinical samples ( 3.3 Translational limitations and clinical challenges Translating the biological insights gained from preclinical studies of DTP reversibility into effective clinical interventions presents additional practical challenges ( 3.4 Risk of inducing stable resistance An additional critical concern when therapeutically exploiting DTP reversibility is the risk of unintentionally facilitating the transition of persister cells into genetically stable, irreversibly resistant populations ( 3.5 Limited preclinical and clinical models Lastly, existing preclinical models inadequately reflect the clinical reality of cancer persistence, limiting their predictive value

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