Optimization Strategies and Synergistic Applications of Engineered Salmonella Typhimurium in Cancer Therapy: From...

The high incidence and mortality of cancer pose significant challenges to clinical treatment. Although established and emerging anticancer therapies have improved outcomes in selected settings, treatment resistance, limited penetration into poorly perfused tumor regions, and immunosuppressive tumor microenvironments remain important challenges in many advanced solid tumors. Salmonella enterica serovar Typhimurium (S. Typhimurium), as a live microorganism inherently endowed with tumor-targeting ability, has emerged as a research hotspot in tumor therapy owing to its unique properties including direct tumor cell killing and activation of anti-tumor immunity. This study systematically reviews the progress of its application in tumor therapy, dissects its intrinsic anti-tumor mechanisms, targeted modification strategies, and combinatorial therapeutic approaches, and discusses the core issues in clinical translation. This review summarizes four nanobiotechnology-based surface-engineering strategies: chemical conjugation, biomineralization, physical adsorption, and biomimetic or polymeric coating. The bacteria-nanomaterial hybrid systems constructed via these methods achieve synergistic complementarity with genetic editing engineering, optimizing the tumor-targeting capacity and therapeutic potential of strains under controllable biosafety conditions. Meanwhile, it summarizes combination regimens of this bacterium with chemoradiotherapy, immunotherapy, and multiple nanotechnology-mediated emerging therapies. Relying on multi-mechanism complementarity, such combinatorial modes break through the bottlenecks of monotherapy and boost the overall anti-tumor efficacy. Finally, we further analyze translational bottlenecks, including interspecies model gaps, administration limitations, and industrial production obstacles, and propose future directions to provide theoretical support for the development of precision bacterial cancer therapeutics.