Synergistic metabolism intervention and immune activation for antitumor therapy by biomineralized lactate oxidase

Abstract

Depleting tumoral lactate is a promising strategy to enhance the immune response and thereby suppressing tumorigenesis. However, the use of lactate oxidase (LOx), the most straightforward lactate-eliminating agent, faces several issues including low stability, no targeting capacity. To solve these problems, a “carrier-free” nanodrug LOx@manganese sulfide (LOx@MnS) was facilely prepared via biomineralization. This way, all the constituents integrated in the nanodrug, including LOx, Mn2+, and hydrogen sulfide (H2S), could be readily delivered into tumor cells and exert their effects. LOx combined with Mn2+ to convert lactate to cytotoxic reactive oxygen species (ROS) through the cascade reaction, meanwhile the crosstalk between H2S and ROS induced metabolism suppression to further augment the therapeutic efficacy. Consequently, the multi-mode modalities evoked by LOx@MnS led to effective induction of immunogenic cell death (ICD) and reversing high-lactate, immunosuppressive microenvironment, suggesting the great potential for anti-tumor immunotherapy. We believe this strategy opens a new avenue to construct functional materials from frangible biomolecules and expand their applications.