GSH‐Responsive Nanoparticles Enhance Hepatocellular Carcinoma Immunotherapy Through Synergistic Effects of Cuproptosis and PI3K Inhibitor Combination

ABSTRACT Cuproptosis, an emerging form of programmed cell death, is capable of inducing mitochondrial dysfunction. Moreover, the PI3K‐AKT‐mTOR signaling pathway contributes to tumor cell progression by reprogramming mitochondrial morphology and function. In this study, we have designed copper complex nanoparticles (NP Cu ) and PI3K‐AKT‐mTOR inhibitor Alpelisib nanoparticles (NP ALP ) that enhance the efficacy of cuproptosis‐based therapies. NP Cu triggers mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), while NP ALP inhibits the PI3K‐AKT‐mTOR signaling pathway to induce apoptosis. The combination of these two nanoparticles (NP Cu +NP ALP ) effectively activates the antitumor responses in the tumor microenvironment (TME). When combined with an anti‐programmed cell death protein 1 antibody (α‐PD‐1), NP Cu +NP ALP significantly inhibits tumor progression and activates antitumor immunity, offering a promising strategy for liver cancer treatment.