Responsive plasmonic hybrid nanorods enables metabolism reprogramming via cuproptosis-photothermal combined cancer therapy

Abstract

Abnormal tumor metabolism leads to tumor growth, metastasis, and recurrence, reprogramming tumor metabolism and activating potent anti-tumor immune response have been demonstrated to have good therapeutic effects on tumor elimination. Copper-based nanomaterials involved in cuproptosis show great prospects in these two aspects, but their efficiency is restricted by Cu homeostasis and the toxicity of the chelator. Here, the pH-responsive AuNRs@Cu₂O core-shell plasmonic hybrid nanorods (ACNRs) have been successfully fabricated to realize microenvironment-controlled release at the tumor site for the combined therapy of cuproptosis and photothermal treatment. The AuNRs core exhibited excellent NIR-II photothermal property, which boost the intracellular concentration of copper to trigger severe cuproptosis and induce immunogenic cell death of tumor cells. In vivo studies demonstrated the ACNR exhibited efficient tumor therapy for primary, metastatic, and recurrent tumors. ACNRs-induced cuproptosis and PTT were capable of reprogramming energy metabolism, leading to a decreased production of lactic acid. This potential of metabolic reprogramming assisted in reshaping the immunosuppressive tumor microenvironment to facilitate the infiltration of immune cells and boost the immune responses triggered by PTT. The therapeutic mechanism was further verified by metabolomics analysis, which indicated that ACNRs + PTT treatment led to the inhibition of the Pentose Phosphate Pathway and Glycolysis pathways in tumor cells. The suppression of glycolytic reduced ATP synthesis, thereby hindering energy-dependent copper efflux, which in turn promoted cuproptosis. Taken together, this study offers promising insights for cuproptosis-based cancer treatment and sheds new light on nanomedicine-mediated metabolic modulation for future tumor therapy.