Metabolic Reprogramming by Engineered Probiotics Potentiates Tumor Chemodynamic Immunotherapy

Area of Science:

• Microbiology
• Immunology
• Biotechnology

Background:

• Engineered bacteria can remodel immunosuppressive tumor microenvironments.
• Bacterial metabolites are key mediators in interkingdom crosstalk but their roles are underexplored.
• Targeting tumor microenvironments is crucial for effective cancer therapy.

Purpose of the Study:

• To develop a programmable probiotic platform using Lactobacillus gasseri (LG) for bladder cancer therapy.
• To investigate the metabolic interplay between LG and tumors.
• To elucidate the mechanisms by which bacterial metabolites modulate the tumor immune microenvironment.

Main Methods:

• Developed a programmable probiotic platform using Lactobacillus gasseri.
• Investigated LG's tumor-colonizing ability and metabolite biosynthesis (H2O2/lactate).
• Analyzed the effects of microbial metabolites, particularly L-leucine, on neutrophil reprogramming and immune cell populations.

Main Results:

• The engineered LG strain effectively colonized tumors and produced H2O2/lactate, optimizing the tumor microenvironment.
• L-leucine reprogrammed neutrophils, suppressing pro-angiogenic neutrophils and activating antigen-presenting CD74+ neutrophils.
• The system induced coordinated immunomodulation, including dendritic cell maturation, M1 macrophage polarization, and enhanced CD8+ T cell and NK cell infiltration.

Conclusions:

• Bacteria-tumor metabolic crosstalk upregulates beneficial metabolites like leucine, promoting neutrophil reprogramming towards an antigen-presenting phenotype.
• This metabolic regulation bridges innate immunity with adaptive antitumor responses.
• Established a metabolism-centric framework for bacteria-mediated cancer immunotherapy, moving beyond material-centric approaches.