An Engineered Bacterium-Based Lactate Bioconsumer for Regulating Immunosuppressive Tumor Microenvironment to Potentiate Antitumor Immunity

Abstract

In this study, a bacterium-based lactate bioconsumer (designated Bac@RFH) was elaborately engineered for persistent lactate consumption to potentiate antitumor immunotherapy. Specifically, Shewanella oneidensis MR-1 was surface-modified with RFH nanoparticles (R848-loaded Fe-TCPP metal–organic framework nanoparticles coated with hyaluronic acid) via covalent borate ester bonds to prepare Bac@RFH bioconsumer, which could specifically target and colonize in tumors to efficiently metabolize intratumoral lactate and concurrently trigger the reduction of the Fe 3+ moieties of RFH through bacteria-mediated electron transfer, resulting in the decomposition of RFH to release Fe 2+ and R848. Moreover, the overexpressed H 2 O 2 in the tumor microenvironment (TME) was catalyzed by the Fe 2+ -driven Fenton reaction to produce cytotoxic ROS, which elicited immunogenic cell death of tumor cells, resulting in DCs maturation and effector T cells activation to eliminate tumors. With the combination of R848-mediated immune activation, Bac@RFH could significantly reshape the immunosuppressive TME for boosting antitumor immunity, such as reducing the recruitment of Tregs and MDSCs as well as promoting the M2-to-M1 polarization of tumor-associated macrophages. In addition, the synergy of Bac@RFH and αPD-1 could evoke robust immune responses to suppress tumor growth and achieve a tumor suppression rate over 90%, which represents a smart strategy to potentiate antitumor immunotherapy via bacterium-based metabolic regulation.