Abstract

Attenuated Salmonella VNP20009 (VNP) shows promising anti-cancer therapeutic potential. Limited understanding of its anti-tumor mechanism has hindered broader clinical application. Recent studies have reported cellular senescence is involved in tumor progression; however, its critical role in VNP therapy remains elusive. Our study revealed that VNP exerts anti-tumor growth and anti-angiogenesis effects by inducing cellular senescence in tumor cells and vascular endothelial cells. While VNP-induced senescence inhibits tumor growth, it concurrently promotes neutrophil extracellular traps (NETs), which paradoxically enhance tumor progression. To address this challenge, we engineered VNP-SNase, a novel variant capable of releasing the DNA-degrading enzyme Staphylococcus aureus nuclease directly within tumors. VNP-SNase significantly inhibited NETs formation across multiple tumor types, effectively promoted anti-tumor immunity, and exhibited improved tumor suppression effects with enhanced biosafety. Our findings elucidate the critical role of cellular senescence in VNP therapy and propose targeting NETs as a strategic approach to enhance the efficacy of VNP-based cancer treatments.