Starving the Aggressor: Recent Advances in Glucose Oxidase-Loaded Nanotherapeutics for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by progression, metastasis, and treatment resistance. Although options include immune checkpoint inhibitors, PARP inhibitors for selected patients, and antibody–drug conjugates, the absence of a single widely applicable molecular target and tumor heterogeneity remain challenges. Increased glycolytic activity in some TNBC tumors provides a rationale for metabolic intervention, although glucose dependence varies among tumors. Glucose oxidase (GOx) catalyzes the oxidation of accessible glucose in the presence of molecular oxygen, generating hydrogen peroxide (H2O2) and gluconic acid. Depending on nanoplatform design and enzyme localization, glucose depletion may occur in the extracellular tumor microenvironment or intracellular compartments following cellular uptake and enzyme release. However, free GOx is limited by poor physiological stability, rapid inactivation, oxygen dependence, inadequate tumor accumulation, and systemic toxicity. Nanotechnology offers strategies to improve enzyme stability and tumor-selective delivery while integrating complementary therapies. Preclinical studies have investigated GOx-loaded nanoplatforms combining metabolic starvation with chemotherapy, chemodynamic therapy, ferroptosis induction, photodynamic and photothermal therapy, radiotherapy, and immunotherapy. Although these platforms demonstrate promising antitumor activity in experimental models, efficacy and proposed mechanisms vary across formulations and models. Pharmacological synergy should be claimed only when supported by quantitative analyses. Tumor heterogeneity, oxygen dependence, toxicity, manufacturing complexity, and regulatory challenges remain major translational barriers. Overall, current findings provide a strong preclinical rationale for further investigation of GOx-loaded nanotherapeutics, but do not establish clinical efficacy in human patients or permit predictions regarding future clinical adoption for TNBC.