Fueling death: Glucose metabolic reprogramming regulates ferroptosis and cuproptosis in cancer

Reprogramming of glucose metabolism is a hallmark of cancer that not only fuels tumor growth but also profoundly regulates cell fate by modulating susceptibility to metal-dependent cell death. This review systematically delineates the mechanistic landscape through which tumor glucose metabolic reprogramming governs ferroptosis and cuproptosis, two emerging forms of regulated cell death driven by iron and copper, respectively. We highlight that glucose metabolism functions as a shared upstream hub, wherein distinct metabolic branches-including glycolysis, the pentose phosphate pathway, the hexosamine biosynthesis pathway, and lactate metabolism-differentially sculpt cellular vulnerability to these death modalities. In ferroptosis, these pathways converge on the NADPH-GSH-GPX4 axis to reinforce antioxidant capacity and lipid remodeling, thereby elevating the ferroptotic threshold. Conversely, cuproptosis sensitivity is dictated by mitochondrial oxidative metabolism and the availability of lipoylated TCA cycle proteins, both of which are suppressed under glycolysis-dominant states. We further discuss how tumor microenvironmental factors, particularly acidification, modulate cuproptosis execution and therapeutic response. Finally, we review emerging therapeutic strategies that leverage metabolic intervention, nanoplatform-based delivery, and combination therapies to exploit these vulnerabilities. By framing glucose metabolism as a central metabolic shunt that regulates the balance between ferroptosis and cuproptosis, this review provides a unified framework for understanding metal-dependent cell death in cancer and offers a roadmap for developing metabolism-targeted combination therapies.