# Integration of _Salmonella_ into Combination Cancer Therapy
## 5 Conclusions  
The present review highlights the unique characteristics of _Salmonella_ as a potential anti-cancer therapeutic agent. The essential tumor targeting capacity, adequate tumor tissue penetration, immunomodulatory effects, and extensive gene packaging capacity, in addition to efficacy in delivering anti-tumor therapeutic agents, suggest _Salmonella_ as a good candidate for combination therapy in cancer. Several pre-clinical studies have demonstrated the enhanced anti-tumor efficacy of conventional and non-conventional cancer therapeutics in combination with attenuated _Salmonella_ in different tumor models. The improved therapeutic outcome was shown in terms of tumor growth retardation, metastasis inhibition, and increased survival rate. Taking everything into consideration, the synergistic effect of combinatorial therapy is thought to be achieved through the ability of _Salmonella_ to (a) improve the delivery and enhance specificity of cancer therapeutic agents to tumor site, (b) increase the antigenicity of tumor cells, and (c) manipulate the immune components of the tumor microenvironment to make it more conducive for improving other therapies, along with its ability to (d) minimize the toxicity associated with other cancer therapies either directly or indirectly by reducing the number of treatment cycles or prolonging the effect of a single treatment (**Figure**3).  
Although the potential of utilizing _Salmonella_ to enhance the outcome of other therapies has been investigated, the mechanistic details underlying combination therapies are still scarce. Additional research is needed to expand the current findings and study the underlying mechanism(s) by which _Salmonella_ improves the therapeutic outcome. Moreover, the modulation of the immune system in combination cancer therapy is worthy of further study because of its essential involvement in cancer development and progression. The increased understanding of the involvement of _Salmonella_ in combinatorial therapies will facilitate the clinical translation of such an approach, thereby potentially ushering in a breakthrough in cancer therapy.  
**Author Contributions:** Conceptualization--B.K.a.-R. and B.H.A.-S.; Investigation--B.H.A.-S.; Visualization--B.H.A.-S. and B.K.a.-R.; Writing--original draft, B.H.A.-S.; Writing--review and editing--B.H.A.-S., M.J.F.-C. and B.K.a.-R.; Supervision--M.J.F.-C. and B.K.a.-R.; Project Administration--B.K.a.-R.; Funding acquisition--B.K.a.-R. All authors have read and agreed to the published version of the manuscript.  
**Funding:** Work in Dr [PERSON]'s laboratory is supported by grants from the Terry Fox Foundation (#11030), the Sheikh Hamdan Award for Medical Sciences (MRG/107/2018), the Zayed Center for Health Sciences (#31R088 and #31R189), the UAEU Program for Advanced Research (#31M193), and the Research Grants Committee (#NP-15-02), College of Medicine and Health Sciences, United Arab Emirates University (to B.K.a.-R).  
**Acknowledgments:** The authors wish to acknowledge United Arab Emirates University, the Shiekh Hamdan Award for Medical Sciences, and the Terry Fox Foundation for supporting this project. B.H.A.-S. is supported by a student scholarship from the Office of Graduate Studies, College of Medicine and Health Sciences, United Arab Emirates University (Al Ain, United Arab Emirates).  
**Conflicts of Interest:** The authors declare no conflict of interest.  
**Abbreviations**  
CAR-T  
Chimeric antigen receptor T cell therapies  
BMCT  
Bacterial-mediated cancer therapy  
TNF-\(\alpha\)  
Tumor necrosis factor-alpha  
PDOX  
Patient-derived orthotopic xenograft  
VEGF  
Vascular endothelial growth factor  
P-gp  
P-glycoprotein MMP-9  
Matrix metalloproteinase 9  
Figure 3: Combination treatments involving _Salmonella_ in cancer. The administration of _Salmonella_ was successful in improving therapeutic outcome of other conventional and non-conventional cancer treatments.