# Integration of _Salmonella_ into Combination Cancer Therapy
### Immunomodulatory Effects  
Along with the intrinsic oncolytic activity of _Salmonella_, its great ability to modulate the immune system also plays a considerable role in tumor inhibition. In this regard, it is worth mentioning that the immunosuppressive tumor microenvironment and immunosurveillance evasion mechanisms are the two major limitations in achieving effective and durable anti-cancer effects. Conventional cancer therapeutics fail to manipulate the immune component of the tumor. On the other hand, _Salmonella_-mediated cancer therapy shows remarkable success in modulating the tumor microenvironment in favor of tumor inhibition. In other words, _Salmonella_ has shown its potential to shift the tumor microenvironment from immunosuppressive to immunogenic. This success is achieved through alterations in both cellular and soluble components of the immune system which, in turn, affect the phenotypic and functional properties of immune cells, as illustrated in **Figure**2. Several studies illustrated _Salmonella_'s ability to increase the tumor-infiltration of different innate and adaptive immune cells, including macrophages [16; 61], natural killer (NK) cells [17], CD4\({}^{+}\) helper T cells [16; 17; 61], CD8\({}^{+}\) cytotoxic T cells [17; 18; 61], and B cells [62]. It is suggested that the recruitment of these immune cells enhances the immune response directed against tumor cells. The enhanced recruitment of neutrophils following _Salmonella_ administration was also documented [17; 49; 58; 63], but it is still not clearly understood whether neutrophil infiltration promotes or inhibits tumor growth [64]. In addition, _Salmonella_ organisms attenuate tumor-induced immunosuppression and inhibit tumor growth by reducing the number of regulatory T cells (Tregs) [65; 66]. _Salmonella_ was also reported to upregulate the expression of pro-inflammatory cytokines and chemokines, including IL-6, IL-1\(\alpha\), IL-17, IL-13, G-CSF, GM-CSF, MIP-1\(\alpha\), and others [67]. This upregulation was attributed to _Salmonella_'s ability to activate the NF-kB pathway [68; 69; 70; 71]. The increased expression of the immunostimulatory factors IL-1\(\beta\), TNF-\(\alpha\), and IFN-\(\gamma\) as well as inducible nitric oxide synthase (iNOS) has been observed following treatment with _Salmonella_[14; 36; 72; 73], which is accompanied by the parallel downregulation of immunosuppressive factors such as IL-4, ARG-1, and TGF-\(\beta\)[36; 74]. It was also reported that _Salmonella_ can transform the immunosuppressive myeloid-derived suppressor cells (MDSCs) into TNF-\(\alpha\)-producing cells [75]. In turn, TNF-\(\alpha\) enhances the infiltration of im  
Figure 2: Schematic diagram illustrating _Salmonella_’s capacity to manipulate immune components of tumor in favor of tumor inhibition. Transformation of the tumor microenvironment from immunosuppressive to immunogenic occurs through increased infiltration and reprogramming of anti-tumor immune cells, upregulating the expression of proinflammatory cytokines and inducing a shift in the phenotypic and functional characteristics of immune cells. The references for the summarized effects are all discussed in the text. MQ: macrophage; IL-1\(\alpha\): interleukin 1 alpha; IL-1\(\beta\): interleukin-1 beta; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte colony-stimulating factor; MIP-1\(\alpha\): macrophage inflammatory protein-1 alpha; ARG-1: arginase-1; TGF- \(\beta\): transforming growth factor-beta; TAMs: tumor-associated macrophages; DC: dendritic cell; M1: M1-like macrophage; M2: M2-like macrophage. mune cells to the tumor site by increasing the permeability of tumor blood vessels [34; 76]. [PERSON] et al. demonstrated _Salmonella_'s ability to reduce the immunosuppressive capacity of intratumoral myeloid cells and highlighted its capacity to induce a shift in the functional characteristics of tumor-associated macrophages (TAMs) toward pro-inflammatory functions [36; 61]. Consistent with these previous findings, [PERSON] et al.