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 H 2 O 2 /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.