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 surfacemodified 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.

Nanomaterials-Involved Tumor-Associated Macrophages’ Reprogramming for Antitumor Therapy

“…Therefore, TAMs were accurately reeducated into M1 phenotype. In addition to using natural or simulated enzymes to downregulate lactate, Zhang and co-workers constructed a bacteria-based nanomaterial (Bac@RFH) as bioconsumer to persistently consume lactate for TAMs’ programming and enhanced immunotherapy . The bacteria Shewanella oneidensis MR-1 was adopted as core component of the bioconsumer, which can metabolize lactate in complex environments.…”

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse

“…Notably, the stimulation of innate immunity by bacteriotherapy has emerged as an effective strategy for mitigating the tumor-specific immunosuppressive microenvironment 18 , 19 . Intracranial bacterial infections promote immune cell recruitment and activation, and bacteria-based immune cell recruitment strategies are feasible for overcoming the “cold” microenvironment of GBM 20 , 21 . GBM-infiltrating bacteria can also activate adaptive immunity by presenting tumor-associated antigens to T cells via bacterial peptides 22 .…”