## 4 _Salmonella_ Promotes Activation of Antitumor Immunity  
The development of various immune evading strategies by tumor cells enabled the generation of more aggressive phenotypes [26]. These highly aggressive phenotypes have led to the establishment of resistance to tumor immune therapy [26; 27]. Systemic administration of _Salmonella_, shown in Figure 1, triggers immune cell infiltration and induction of proinflammatory cytokine expressions such as IL-1\(\beta\) and TNF-\(\alpha\)[5; 28]. Also, macrophages in _Salmonella_-colonized tumor express and activate the inflammasome pathway involving NLRP9, IPAF and caspase-1 p10 [29]. When _Salmonella_ gained access to the tumor microenvironment, intratumoral CD11b\({}^{+}\) myeloid cells accumulate and are soaked to undergo phenotypic and functional maturation, impairing their suppressive activity [30; 31]. The decrease in suppressive activity after _Salmonella_ treatment involves downregulation of immunosuppressive factors, particularly arginase-1, IL-4, TGF-\(\beta\), and VEGF, and an enhanced expression of inducible nitric oxide synthase (iNOS) and IFN-\(\gamma\)[31]. The enhanced expressions of iNOS, IFN-\(\gamma\) and other IFN-inducible chemokines may play a crucial role in the recruitment of neutrophils, activated CD8+ T cells and an increase in intratumoral activated NK cells [31; 32; 33]. It was previously reported that TLR4 signaling is involved in the _Salmonella_-induced cytokine expression [32] and that the lipopolysaccharide-LPS of _Salmonella_ might be crucial in the activation and recruitment of immune cells and the subsequent production primarily of TNF-\(\alpha\)[34]. In a recent study, an engineered _S. typhimurium_ strain secreting heterologous flagellin B (FlaB) in tumor tissues first induced the recruitment of infiltrating immune cells via TLR4 signaling followed by the activation of the recruited intratumoral macrophages via TLR5 signaling which appears to have caused the increase in the synthesis of cytotoxic mediators and cytokines [35]. In another study, the flagellin of _S. typhimurium_ fused with peptide P10 of the gp43 protein from _Paracoccidioides brasiliensis_ activated TLR5 signaling that helped impair the metastatic activity of melanoma in vivo [36]. Bacterial LPS and the enhanced synthesis of TNF-\(\alpha\) induced the activation of CD8+ T cell that plays a major role in tumor regression [34], consistent with the findings that the antitumor activity of host immune system involves both CD4+ and CD8+ T cells rather than solely relying on innate mechanisms [37; 38]. Lysis of tumor cells by anti-_Salmonella_-specific T cells further recruits infiltration of CD8+ T in _Salmonella_-colonized tumor that might eventually result in the uptake of tumor debris by antigen-presenting cells leading to presentation to naive T cells and activation of tumor-specific T cells [7; 39; 37]. Previous reports have already pointed out that bacteria-induced gap junctions, such as connexin-43 (Cx43), can be formed between tumor and dendritic cells and promote tumor antigen cross-presentation [40]. The upregulation of Cx43 in tumor after _Salmonella_ treatment explains tumor antigen cross-presentation leading to immune cell-mediated antitumor activity [41]. The activation of antitumor immunity mediated by _Salmonella_ treatment does not rely only on the recruitment of a variety of infiltrating immune cells as mentioned previously. Interestingly, _Salmonella_ invasion of tumor tissue interferes with the immunosuppressive nature of tumor microenvironment in a variety of mechanisms [5; 7]. The immunosuppressive factors arginase-1, IL-4, TGF-\(\beta\), and VEGF were known to be upregulated in many solid tumors but were found to be downregulated following _Salmonella_ treatment [31]. Another immunosuppressive factor, the indoleamine 2, 3-dioxygenase 1 (IDO), is involved in mediating activation of regulatory T cells by increasing kynure concentration [42].