Cascade-amplified cuproptosis in hepatocellular carcinoma via a smart hollow mesoporous CuS nanoplatform enabling synergistic phototherapy/chemodynamic therapy/starvation therapy

Abstract

Emerging copper-mediated lethal mechanisms provide cancer therapies, with current research emphasizing precise copper regulation to enhance its dual role in tumor pathology. Here, we presented a bimetallic nanoplatform, HMCuS/Ru/ICG/GOx@9R-P201Ti (HRIG9R), designed to amplify cuproptosis for hepatocellular carcinoma (HCC) therapy. Upon 808 nm near-infrared (NIR) irradiation, the mild photothermal effect enhanced cytotoxic T-cell differentiation. Concurrently, glucose oxidase (GOx) depletes glucose and generated hydrogen peroxide (H2O2), fueling Ru-mediated chemodynamic therapy (CDT) and reducing Cu2+ to toxic Cu+ to potentiate cuproptosis. This synergistic cascade — integrating starvation, CDT, and adenosine triphosphate (ATP) depletion — reprogramed the tumor immune microenvironment and induced immunogenic cell death (ICD). These findings highlight the HMCuS/Ru/ICG/GOx@9R-P201Ti nanoplatform as a potent strategy to enhance cuproptosis-based anticancer immunotherapy.