# Integration of _Salmonella_ into Combination Cancer Therapy
## 3 _Salmonella_ in Combination with Other Approaches to Cancer Therapy  
### Combination with Chemotherapeutic Agents  
The efficacy of chemotherapy is partly limited by systemic toxicity, lack of selectivity for cancer cells, and the chances of drug resistance development. In order to overcome these limitations, the role of _Salmonella_ in enhancing the efficacy of chemotherapeutic agents against different tumor models has been investigated. [PERSON] et al. reported that the intra-tumoral administration of an attenuated strain of _S. typhimurium_ improved the outcomes of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in non-Hodgkin lymphoma-bearing mice, with an overall decrease in toxicity [100]. In this model, the combination therapy successfully inhibited tumor growth and prolonged animal survival compared with either treatment alone, and was associated with an increase in the percentage of CD8+ tumor-infiltrating lymphocytes (TILs) as well as in the cytotoxic ability of NK cells [100]. In a study using breast cancer cells, mice treated intravenously with attenuated _S. typhimurium_ plus a low dose of doxorubicin exhibited a slower tumor growth rate in comparison to those treated with single therapy [101]. It is worth noting that mice treated with the maximum tolerated dose of doxorubicin showed greater delay in tumor growth, but this was at the cost of higher toxicity [101]. It was also suggested that _Salmonella_/doxorubicin combination enhances the infiltration of CD8+ T cells and Tregs to the tumor site and increases the ratio of Mo-MDSCs/G-MDSCs within spleen and tumor tissues [101]. A study conducted by [PERSON] et al. documented that the intraperitoneal administration of attenuated _Salmonella choleraeus_ improved the outcome of cisplatin therapy in hepatoma- and lung tumors-bearing mice [102]. This combination induced changes in the tumor microenvironment, including an increase in the infiltrating neutrophils, CD8+ T cells, and apoptotic cells [102]. [PERSON] and his group highlighted the ability of _S. typhimurium_ A1-R to enhance the anti-tumor capacity of gemcitabine among nude nice bearing pancreatic cancer PDOX [103], although gemcitabine has limited efficacy in treating pancreatic cancer. Another group succeeded in utilizing an attenuated _S. typhimurium_ strain VNP20009 to improve the outcome of the standard maximum tolerated dose and lose-dose metronomic cyclophosphamide chemotherapy in B16F10 melanoma-bearing mice [104]. [PERSON] et al. also described the improved anti-tumor effect of VNP20009 combined with triptolide in a mouse melanoma model [67]. This improvement was attributed to the enhanced capacity of combination therapy to suppress tumor angiogenesis and reduce the level of serum and tumor VEGF in comparison to either treatment alone [67; 104]. In contrast to [PERSON] et al., [PERSON] et al. showed that combination therapy reduced tumor-infiltrating neutrophils [67]. They reported that VPN20009 alone attracted neutrophils to tumor site, but this recruitment was inhibited by the anti-inflammatory compound triptolide [67]. Interestingly, the preferential accumulation of _Salmonella_ in tumor was further enhanced by the combination therapy in comparison to _Salmonella_alone [67; 102; 104]. This could be explained by the ability of the _Salmonella_-chemotherapy combination to reduce tumor microvascularization and provide a more hypoxic microenvironment that is conducive to _Salmonella_'s colonization and proliferation [67; 104]. Moreover, a study that utilized the combination of attenuated _S. typhimurium_ and carboplatin against metastatic cancer of unknown primary (CUP) reported the ability of the combination to significantly inhibit tumor growth compared to monotherapy treatment [105]. **Table 1** shows a summary of representative studies that utilized _Salmonella_ in combination with chemotherapeutic drugs to treat cancer.