# Integration of _Salmonella_ into Combination Cancer Therapy
###### Abstract  
Current modalities of cancer treatment have limitations related to poor target selectivity, resistance to treatment, and low response rates in patients. Accumulating evidence over the past few decades has demonstrated the capacity of several strains of bacteria to exert anti-tumor activities. _Salmonella_ is the most extensively studied entity in bacterial-mediated cancer therapy, and has a good potential to induce direct tumor cell killing and manipulate the immune components of the tumor microenvironment in favor of tumor inhibition. In addition, _Salmonella_ possesses some advantages over other approaches of cancer therapy, including high tumor specificity, deep tissue penetration, and engineering plasticity. These aspects underscore the potential of utilizing _Salmonella_ in combination with other cancer therapeutics to improve treatment effectiveness. Herein, we describe the advantages that make _Salmonella_ a good candidate for combination cancer therapy and summarize the findings of representative studies that aimed to investigate the therapeutic outcome of combination therapies involving _Salmonella_. We also highlight issues associated with their application in clinical use. Salmonella; cancer; combination therapy; immunotherapy 2021 13 3228 10 May 2021 24 June  
to the development of immune-related adverse effects [3]. These obstacles reduce the capacity of cancer therapies to achieve the optimum therapeutic outcome and therefore underscore the increasing demand to develop better strategies for cancer treatment. Bacterial-mediated cancer therapy (BMCT) was recognized in the 19 th century when [PERSON] first noticed tumor regression in cancer patients with gas gangrene [4]. Subsequently, [PERSON] succeeded in utilizing heat-inactivated _Streptococcus pyogenes_ and _Serratia marcescens_ to treat inoperable tumors, providing BMCT as one of the first examples of cancer immunotherapy [5,6]. Despite the achieved success, BMCT gradually disappeared from clinical use due to criticisms of [PERSON]'s toxin along with the rise of chemotherapy and radiotherapy as effective cancer treatments. The development of molecular biology in addition to the increased understanding of host-pathogen interactions and tumor biology reinspired the interest of researchers toward utilizing bacteria as an anti-cancer therapeutic agent. Outstanding and promising candidates for BMCT include _Bacillus_ Calmette-Guerin, _Listeria monocytogenes_, _Salmonella enterica_ serovar Typhimurium (hereafter _S. typhimurium  
tumor cylindroids, with penetration of tissue and induction of necrosis [29]. Furthermore, it has been shown that motility is essential for bacterial accumulation in tumor tissues [32]. However, another study proposed that the accumulation of _Salmonella_ in tumors is influenced by the tumor microenvironment, host reticuloendothelial system, and bacterial metabolism, and is independent of its chemotactic and mobile properties [33]. A third study attributed the initial colonization in tumor tissues to tumor necrosis factor alpha (TNF-\(\alpha\)) induced by the intravenous administration of _Salmonella_[34]. The increased level of TNF-\(\alpha\) induced an increase in blood influx to the tumor, thereby enhancing the colonization of _Salmonella_ in tumor tissue [34]. Irrespective of the exact mechanism, the targeted distribution and proliferation of _Salmonella_ in tumor tissues overcome the lack of tumor specificity and inadequate tissue penetration, which are the major limiting factors for the therapeutic efficacy of conventional cancer therapies. Moreover, the replication potential of this biological agent allows its administration at low dose and frequency, thereby minimizing toxicity and adverse side effects. Figure 1: _Salmonella_ characteristics that favor their use in cancer therapy. (**A**) The major modalities of cancer treatment. (**B**) The 5 key properties of _Salmonella_ organisms that make them amenable for potential use in cancer therapy.