Lactate‐Oxidase‐Instructed Cancer Diagnosis and Therapy

Abstract

Lactate oxidase (LOx) has attracted extensive interest in cancer diagnosis and therapy in recent years owing to its specific catalysis on l‐lactate; its catalytic process consumes oxygen (O2) and generates a large amount of hydrogen peroxide (H2O2) and pyruvate. Given high levels of lactate in tumor tissues and its tight correlation with tumor growth, metastasis, and recurrence, LOx‐based biosensors including H2O2‐based, O2‐based, pH‐sensitive, and electrochemical have been designed for cancer diagnosis, and various LOx‐based cancer therapy strategies including lactate‐depletion‐based metabolic cancer therapy/immunotherapy, hypoxia‐activated chemotherapy, H2O2‐based chemodynamic therapy, and multimodal synergistic cancer therapy have also been developed. In this review, the lactate‐specific catalytic properties of LOx are introduced, and the recent advances on LOx‐instructed cancer diagnostic or therapeutic platforms and corresponding biological applications are summarized. Additionally, the challenges and potential of LOx‐based nanomedicines are highlighted.

The Biocatalysis in Cancer Therapy

“…Others. Similar to GOs, there are more than 180 enzymes in BRENDA Enzyme Database that could generate H 2 O 2 as a product by biocatalytic oxidation of various substances, 155 such as alcohol oxidases (AOs), 156 pyranose oxidases (P2Os) (using glucose), 157 L-amino-acid oxidases (LAAOs), 150 and L-lactate oxidases (LOs) 158 (Figure 12D−F).…”

“…Similar to GOs, there are more than 180 enzymes in BRENDA Enzyme Database that could generate H 2 O 2 as a product by biocatalytic oxidation of various substances, such as alcohol oxidases (AOs), pyranose oxidases (P2Os) (using glucose), l -amino-acid oxidases (LAAOs), and l -lactate oxidases (LOs) (Figure D–F). The LAAOs have been applied in cancer therapy by deletion of essential amino acids and generation of toxic ROS in the TME, such as lysine oxidases for the treatment of leukemia, prostate cancer, and colorectal adenocarcinoma .…”

Manganese Dioxide-Entrapping Dendrimers Co-Deliver Protein and Nucleotide for Magnetic Resonance Imaging-Guided Chemodynamic/Starvation/Immune Therapy of Tumors

“…For example, cancer has high demand of glucose as a nutrient source, which undergoes active glycolysis to result in lactate accumulation in the TME. In this context, the use of natural enzymes such as glucose oxidase (GOx) 20 or lactate oxidase (LOx) 21 to catalyze the nutrient or metabolite has been recognized as a promising strategy to starve the cancer cells. 22 Importantly, the catalytic process of these enzymes increases the level of oxidative H 2 O 2 in TME, to coordinate with transition-metal-ion-based Fenton or a Fenton-like reaction.…”

Regulation of Tumor Lactate Metabolism by Targeting Glycolysis and Mitochondrial OXPHOS for Tumor Metastasis Inhibition

“…Lactate is a key molecule causing tumor metastasis because it not only induces angiogenesis by promoting the secretion of vascular endothelial growth factor (VEGF) but also creates an immunosuppressive tumor microenvironment (TME) by promoting the polarization of M2 macrophages and inhibiting the function of cytotoxic T cells. , Currently, efflux inhibition of intracellular lactate , and depletion of extracellular lactate , were common methods to reverse lactate-correlated tumor metastasis. However, these strategies that focused on lactate already produced are flawed since it is a symptomatic treatment and fails to cut off the source of lactate production.…”