The genes slyA, STM3120 and htrA are required for the anticancer ability of VNP20009

Area of Science:

• Oncology
• Microbiology
• Immunology

Background:

• VNP20009 is an effective anti-cancer agent with tumor-targeting capabilities.
• The correlation between tumor targeting and anti-cancer efficacy was previously assumed.

Purpose of the Study:

• To investigate the mechanism behind VNP20009's anti-cancer activity.
• To determine if bacterial tumor colonization or host immune response is crucial for VNP20009 efficacy.

Main Methods:

• Generation and analysis of VNP20009 mutant strains (ΔslyA, ΔSTM3120, ΔhtrA).
• Assessment of bacterial fitness in normal tissues and tumors.
• Evaluation of anti-cancer capacity, immune cell infiltration, and cytokine expression (TNF-α, IL-1β) in tumors.

Main Results:

• Mutant strains showed reduced fitness in normal tissues but maintained fitness in tumors.
• Mutant strains exhibited partial or complete loss of anti-cancer capacity.
• Genes slyA, STM3120, and htrA are essential for bacterial survival in macrophages and tumor microenvironment remodeling.
• Reduced immune cell infiltration and decreased TNF-α and IL-1β mRNA levels were observed in tumors treated with mutant strains.

Conclusions:

• Bacterial cancer therapy efficacy, exemplified by VNP20009, is primarily driven by elicited immune responses, not bacterial load within tumors.
• The genes slyA, STM3120, and htrA are critical for VNP20009 to modulate the tumor immune microenvironment.
• This study offers a new perspective on the mechanisms underlying bacterial cancer therapy.