Leveraging dysregulated tumor metabolism for targeting anticancer bacteria

Area of Science:

• Microbiology
• Oncology
• Biotechnology

Background:

• Bacterial cancer therapy requires enhanced tumor specificity for safety and efficacy.
• Tumors exhibit altered metabolism, including elevated kynurenine, a potential targeting mechanism.

Purpose of the Study:

• To engineer bacteria that specifically target tumors based on kynurenine accumulation.
• To develop a novel bacterial therapeutic with improved tumor specificity and anticancer properties.

Main Methods:

• Engineered *Escherichia coli* with a kynurenine-responsive regulator (KynR) and promoter.
• Optimized KynR expression, transporter activity, and signal amplification for kynurenine detection.
• Modified *Salmonella enterica* growth using kynurenine-controlled circuits for cell wall synthesis.

Main Results:

• Achieved bacterial response to low micromolar kynurenine levels.
• Developed kynurenine-controlled *S. enterica* (AD95+) with superior tumor specificity in murine models.
• Demonstrated AD95+ anticancer properties in preclinical models.

Conclusions:

• Engineered bacteria targeting tumor-specific kynurenine metabolism show promise for cancer therapy.
• AD95+ exhibits enhanced tumor targeting and therapeutic potential compared to existing strains.
• This strategy offers a new avenue for developing safer and more effective bacterial cancer treatments.