Sialidase-Chimeric Bioengineered Bacteria for Tumor-Sialoglycan-Triggered Solid Tumor Therapy

Area of Science:

• Synthetic Biology
• Bacterial Therapeutics
• Cancer Immunotherapy

Background:

• Adoptive cell therapies face challenges in solid tumor treatment, including antigen specificity, tissue infiltration, and cell exhaustion.
• Bacterial cells offer inherent advantages for tumor targeting, deep penetration, and high bioactivity, presenting a promising alternative.

Purpose of the Study:

• To engineer bacteria with a responsive gene circuit for targeted cancer cell lysis.
• To overcome the limitations of current adoptive cell therapies for solid tumors.
• To investigate the potential of bacterial desialylation in reversing tumor immunosuppression.

Main Methods:

• Engineered *Escherichia coli* MG1655 with a sialic-acid-responsive gene circuit to express hemolysin E (HlyE).
• Bioorthogonal decoration of bacterial surfaces with sialidases for recognizing and cleaving tumor sialoglycans.
• Utilized free sialic acids as chemical inducers to activate HlyE production and tumor cell lysis.

Main Results:

• Engineered bacteria successfully produced HlyE in response to sialic acids, leading to tumor cell lysis.
• The system mimics CAR-T cell function but overcomes limitations of adoptive cell therapies.
• Sialidase-mediated desialylation reversed immunosuppressive glycoimmune checkpoints, enhancing anti-tumor effects.

Conclusions:

• Engineered bacteria with a responsive gene circuit represent a novel strategy for solid tumor treatment.
• This approach offers a potential solution to the challenges associated with adoptive cell therapies.
• Bacterial desialylation can modulate the tumor microenvironment and improve therapeutic outcomes.