Targeting Glucose Metabolism: Synergistic Strategies to Enhance Apoptosis and Immune Activation in Hepatocellular Carcinoma Treatment

Exploiting the dependency of cancer cells on glycolysis offers a promising avenue to enhance therapeutic strategies for hepatocellular carcinoma (HCC). In our study, we employ glucose oxidase (GOx) as a glucose metabolism modulator to deplete glucose within the tumor microenvironment, initiating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and regulating both death receptor and mitochondrial apoptosis pathways, subsequently sensitizing HCC cells to DOX- induced apoptosis. DOX, co-formulated with GOx in nanoparticle (GOx-DOX-NP), not only substantially reduces tumor volume and increases number of apoptotic cells in tumors, but also acts as an immunogenic cell death (ICD) inducer, stimulating anti-tumor immunity. This effect further improves the immunotherapy. In conclusion, our findings underscore the potential of integrating glucose metabolism modulation with apoptosis-based therapies and immunotherapy for more effective liver cancer treatment. Comparative gene expression profiling analysis of RNA-seq data for murine HCC tumors with or without treatment of GOX-DOX nanoparticles