Microwave-responsive, energy-metabolism-regulating nanosystem for tumor treatment through co-promotion of cuproptosis/ferroptosis.

Metal ions play a crucial role in the initiation and progression of tumor cells. Imbalances in metal ion homeostasis within tumor cells may have lethal effects on these cells. In recent years, newly discovered forms of cell death, such as ferroptosis and cuproptosis, have opened up new avenues for improving tumor treatment strategies. However, the abnormal metabolic patterns of tumor cells make it difficult for metal ion-mediated non-apoptotic cell death to fully exert its therapeutic effects. Therefore, this study proposes a copper metal-organic framework (MOF)-based nanoparticle (MOF-199@Shikonin@hyaluronic acid-amino polyethylene glycol thiol) designed to trigger metal ion-mediated non-apoptotic cell death by regulating the abnormal energy metabolism of tumor cells. Shikonin, an inhibitor of pyruvate kinase M2, modulates the abnormal metabolism of tumor cells by inhibiting glycolysis and restoring normal tricarboxylic acid cycle function, thereby influencing glutathione production. The synergistic introduction of large amounts of copper ions sensitizes tumor cells to cuproptosis and directly disrupts the redox balance of the tumor microenvironment, thereby inducing ferroptosis. Overall, the remodeling of tumor metabolism is expected to enhance the sensitivity to metal ion-mediated non-apoptotic cell death and improve treatment efficacy against tumors.