Cuproptosis Sensitizer Disrupting Mutual Maintenance of Triple Homeostasis for Enhanced Tumor Therapy

ABSTRACT The cuproptosis efficacy is severely hampered by robust Cu homeostasis in tumors, including glutathione (GSH)‐mediated chelation and ATP7B‐mediated efflux. Besides, the interconnection among Cu ion, redox, and energy metabolism homeostasis also increases the therapy resistance. Herein, a novel strategy to disrupt this mutual maintenance of triple homeostasis using Cu‐based nanoparticles (Cu‐LND‐FeE) was developed, which was loaded with glycolysis inhibitor lonidamine (LND) and modified by Fe‐polyphenol. Specifically, Fe ions were first released to generate reactive oxygen species (ROS), disrupting redox homeostasis and triggering ferroptosis. Meanwhile, GSH was consumed by ROS to block Cu ion chelation. Moreover, LND suppressed ATP production, weakening ATP7B function to block Cu ion efflux. These effects collectively disrupted Cu ion homeostasis and ultimately reinforced cuproptosis. More importantly, the inhibition of glycolysis together with mitochondrial damage inflicted by ferroptosis and cuproptosis synergistically disrupted energy metabolism homeostasis, creating a self‐amplifying therapeutic cycle. Briefly, besides sensitizing cuproptosis, the developed triple homeostasis disruption strategy in this study exhibits great promising potential in highly efficient tumor therapy.