Reprogramming a Doxycycline-Inducible Gene Switch System for Bacteria-Mediated Cancer Therapy

Area of Science:

• Microbiology
• Oncology
• Biotechnology

Background:

• Attenuated Salmonella typhimurium demonstrates potential as an antitumor agent by colonizing and inhibiting tumor growth.
• Developing controllable systems for bacterial-based cancer therapies is crucial for maximizing efficacy and minimizing off-target effects.

Purpose of the Study:

• To engineer a doxycycline (Doxy)-inducible gene switch system in attenuated S. typhimurium.
• To evaluate the therapeutic efficacy of this system in preclinical tumor models.

Main Methods:

• A Doxy-inducible gene switch system was constructed using two plasmids to control cargo gene expression (Rluc8, clyA).
• Transformed S. typhimurium was administered intravenously to tumor-bearing mice (CT26 and MC38 models).
• Bioluminescence imaging tracked bacterial tumor targeting, and tumor growth suppression was assessed post-Doxy induction.

Main Results:

• The Doxy-inducible system successfully triggered cargo gene expression (Rluc8, clyA) specifically in tumors.
• Tumor colonization and payload expression were confirmed via bioluminescence imaging after Doxy administration.
• Bacteria expressing clyA significantly suppressed tumor growth and prolonged survival, even after a single Doxy induction.

Conclusions:

• Attenuated S. typhimurium with the novel Doxy-inducible gene switch system exhibits significant antitumor therapeutic effects.
• A single induction of the gene switch system can elicit potent anti-tumor responses.
• This engineered Salmonella strain represents a promising biotherapeutic agent for cancer treatment.