Dual metabolism-disrupted nanoparticles for reprogramming the immune microenvironment to potentiate cuproptosis immunotherapy

Reprogramming the metabolism-mediated tumor microenvironment is a promising strategy to revitalize antitumor immunity. However, single metabolic modulation is often insufficient to achieve significant antitumor effects due to the intricate metabolic mechanisms in tumors. This study fabricated dual metabolism-disrupted carrier-free nanoparticles (LN NPs) <i>via</i> copper coordination-driven assembly of a glycolysis inhibitor and an indoleamine-pyrrole 2,3-dioxygenase 1 inhibitor. After intravenous administration, LN NPs effectively accumulated at tumor sites to enhance the bioavailability of therapeutic agents. They simultaneously disrupted glycolysis and amino acid metabolism, resulting in a reduction in the levels of inhibitory metabolites and alleviating tumor immunosuppression. Furthermore, the inhibition of glycolysis generating reactive oxygen species, and copper-triggered cuproptosis synergistically induced potent immunogenic cell death. Subsequently, LN NPs elicited a robust cascade of immunological responses that effectively inhibited tumor growth and metastasis. Overall, this study offered a promising paradigm for tumor treatment via the synergistic dual metabolic modulation and cuproptosis immunotherapy.