Stimuli-Responsive Nanozyme Reprograms Tumor Immunometabolism and Overcomes Therapeutic Resistance in Hepatocellular Carcinoma

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.