Lactate oxidase/vSIRPα conjugates efficiently consume tumor-produced lactates and locally produce tumor-necrotic H2O2 to suppress tumor growth

Abstract

Aggressive tumor formation often leads to excessive anaerobic glycolysis and massive production and accumu-lation of lactate in the tumor microenvironment (TME). To significantly curb lactate accumulation in TME, in this study, lactate oxidase (LOX) was used as a potential therapeutic enzyme and signal regulatory protein alpha variant (vSIRP alpha) as a tumor cell targeting ligand. SpyCatcher protein and SpyTag peptide were genetically fused to LOX and vSIRP alpha, respectively, to form SC-LOX and ST-vSIRP alpha and tumor-targeting LOX/vSIRP alpha conjugates were constructed via a SpyCatcher/SpyTag protein ligation system. LOX/vSIRP alpha conjugates selectively bound to the CD47-overexpressing mouse melanoma B16-F10 cells and effectively consumed lactate produced by the B16-F10 cells, generating adequate amounts of hydrogen peroxide (H2O2), which induces drastic necrotic tumor cell death. Local treatments of B16-F10 tumor-bearing mice with LOX/vSIRP alpha conjugates significantly suppressed B16-F10 tumor growth in vivo without any severe side effects. Tumor-targeting vSIRP alpha may allow longer retention of LOX in tumor sites, effectively consuming surrounding lactate in TME and locally generating adequate amounts of cytotoxic H2O2 to suppress tumor growth. The approach restraining the local lactate concentration and H2O2 in TME using LOX and vSIRP alpha could offer new opportunities for developing enzyme/ targeting ligand conjugate-based therapeutic tools for tumor treatment.