Dual Energy Depletion by Zinc/Copper Disruptor to Potentiate Cuproptosis and Pyroptosis for Enhanced Tumor Immunotherapy.

Abstract

Metal ion interference therapy disrupts ion homeostasis to stimulate immunity, but the underlying mechanisms remain poorly elucidated. Here, a hydrazide hyaluronan-decorated copper/zinc disruptor is constructed to inhibit tumoral energy metabolism and activate anticancer immunity. Functionally, Zn²⁺ acts as a metabolic inhibitor to suppress glycolysis by directly restraining lactate dehydrogenase activity and downregulating the PI3K/Akt/HIF-1α axis, thus reducing lactate output and limiting adenosine triphosphate generation. In parallel, Cu²⁺ triggers cuproptosis via mitochondrial proteotoxicity and lipoylated protein aggregation, thereby blocking the flux of pyruvate into the tricarboxylic acid cycle and aggravating energy exhaustion. This metabolic collapse forms a mechanistic cascade, in which glycolytic inhibition predisposes cells to cuproptotic stress, while cuproptosis further reinforces pyroptotic activation. Ultimately, ion overload, severe energy deficit, and subsequent oxidative perturbation cooperatively amplify pyroptosis-driven inflammatory cytokine release and establish a synergistic metal ion-induced immunogenic cell death pathway. In vitro studies reveal that the anticancer activity of the disruptor involves oxidative stress, mitochondrial dysfunction, and inflammatory responses. In vivo studies demonstrate that it efficiently suppresses primary and distant tumor growth and activates systemic immunity. Collectively, this bimetallic disruption strategy bridges metal therapy with immunotherapy, provides insights into the underlying molecular mechanisms, and highlights the potential of metal-based nanomedicine for tumor immunotherapy.