Abstract
Hepatocellular carcinoma (HCC) exhibits profound glycolytic reprogramming that drives tumor growth, impairs apoptosis, and suppresses immune responses, leading to resistance against conventional therapies. To overcome this challenge, we developed a stimuli-responsive nanozyme composed of a pH-sensitive lipid-gelatin-protamine (LGP) nanogel encapsulating glucose oxidase (GOx). This tumor-selective nanozyme depletes intratumoral glucose under acidic conditions, inducing oxidative and endoplasmic reticulum stress, upregulating death receptors, and sensitizing HCC cells to TRAIL- and doxorubicin (DOX)-induced apoptosis. Co-delivery of GOx and DOX within the nanozyme reprograms tumor immunometabolism, enhancing immunogenic cell death and promoting the release of damage-associated molecular patterns (DAMPs). These changes stimulate dendritic cell maturation and cytotoxic CD8
T-cell activation. Transcriptomic profiling confirms that this nanozyme remodels the immunosuppressive microenvironment by suppressing metabolic pathways while activating immune-related gene programs. When combined with an anti-PD-1 checkpoint blockade, the nanozyme elicits potent tumor regression and abrogates metastasis without systemic toxicity in orthotopic HCC models. Overall, this work introduces a multifunctional tumor-responsive nanozyme that integrates metabolic intervention, apoptotic priming, and immune activation to overcome therapeutic resistance in the HCC.