Metabolic Reprogramming by Engineered Probiotics Potentiates Tumor Chemodynamic Immunotherapy.

Abstract

Engineered bacteria hold promise for remodeling immunosuppressive tumor microenvironments through innate immunogenicity and localized therapeutic delivery. While bacterial-derived metabolites are increasingly recognized as key mediators, their specific roles in interkingdom crosstalk remain underexplored. Here, we develop a programmable probiotic platform leveraging Lactobacillus gasseri (LG)-tumor metabolic interplay to potentiate bladder cancer therapy. The selected LG strain demonstrates superior tumor-colonizing ability and intrinsic H₂O₂/lactate biosynthesis, creating an optimal tumor microenvironment for hemoglobin-modified MnOx nanoparticles to enhance chemodynamic therapy efficacy. Mechanistically, microbial metabolites, including L-leucine, orchestrate neutrophil phenotypic reprogramming by suppressing pro-angiogenic dcTRAIL-R1⁺ neutrophils while activating antigen-presenting CD74⁺ neutrophil populations. The engineered system elicites coordinated immunomodulation through multiple mechanisms: (1) promoting dendritic cell maturation, (2) increasing CD74⁺ neutrophil populations, (3) inducing macrophage polarization from M2 to M1 phenotypes, and (4) enhancing tumor infiltration of CD8⁺ T cells and natural killer cells. This study reveals that bacteria-tumor metabolic crosstalk upregulates beneficial metabolites, notably leucine, which promotes phenotypic reprogramming of neutrophils toward the antigen‑presenting CD74⁺ subset, thereby bridging innate metabolic regulation with adaptive antitumor immunity. This finding goes beyond the material-centric logic of previous probiotic-nanomaterial systems and establishes a metabolism-centric framework for bacteria‑mediated cancer immunotherapy.