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

## TL;DR

A smart nanozyme targets liver cancer by altering its metabolism and boosting the immune response, overcoming treatment resistance.

## Contribution

A stimuli-responsive nanozyme that reprograms tumor immunometabolism and overcomes therapeutic resistance in HCC.

## Key findings

- The nanozyme depletes glucose in tumors, inducing stress and sensitizing HCC cells to apoptosis.
- Co-delivery of GOx and DOX promotes immunogenic cell death and activates immune cells.
- Combining the nanozyme with anti–PD-1 therapy leads to tumor regression and reduced metastasis in HCC models.

## 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.