# Integration of _Salmonella_ into Combination Cancer Therapy
## 3 _Salmonella_ in Combination with Other Approaches to Cancer Therapy
### Combination with Radiotherapy  
Radiotherapy is a conventional cancer treatment in which \(\sim\)50% of cancer patients receive radiation during the course of the disease [113]. However, radiotherapy-associated limitations obstruct achieving favorable therapeutic outcome without causing toxicity to normal tissues. _Salmonella_ has been combined with radiotherapy aiming to enhance the overall efficacy of the treatment. In a study conducted in 2014, [PERSON] et al. utilized _S. typhimurium_ to increase the radiosensitivity of the radio-resistant melanoma model [114]. They documented the success of _Salmonella_ and gamma radiation combination and its ability to induce greater apoptosis in B16F10 cells in comparison to radiotherapy alone or _Salmonella_ alone [114]. They also showed that the combinatorial treatment resulted in a significant inhibition of tumor growth in melanoma-bearing mice, and a prolonged survival rate compared to monotherapy [114]. Other groups performed studies in which engineered _Salmonella_ was combined with radiotherapy. The combination of lipid A mutant _S. typhimurium_ and X-rays resulted in a supra-additive therapeutic effect in B16F10 or Cloudman S91 melanoma-bearing mice [115]. Other studies demonstrated an improved CT26 tumor growth inhibition when treated with a combination of _S. typhimurium_ strain \(\Delta\)ppGpp/pBAD-ClyA and radiotherapy, highlighting the contribution of radiotherapy to the colonization of _Salmonella_ in tumor tissues [116]. [PERSON] et al. intended to improve specificity and anti-tumor therapeutic ability against malignant melanoma by taking advantage of the preferential colonization of _Salmonella_ strain VNP20009 in the hypoxic tumor tissues and coating this bio-therapeutic agent with the photothermal agent polydopamine [117]. In this therapy, the systemic administration of _Salmonella_ helped in the delivery of poly-dopamine to hypoxic and poorly vascularized regions of the tumor. Thereafter, when tumor tissue was irradiated, polydopamine helped in the conversion of near-infrared light into heat, which then increased the local temperature and eventually killed the surrounding cancerous cells, leading to tumor growth inhibition. The authors brought attention to the ability of this combination to substantially eliminate melanoma tumors without relapse [117]. The combinatorial therapy also resulted in a higher level of apoptosis in melanoma tumors and a greater induction of cytokine secretion, which contributed to the enhanced anti-tumor effect. Attenuated _Salmonella typhi_ Ty21a was also an excellent vehicle to deliver gold nanoparticles to the radio-resistant central hypoxic regions of CT-26 colon cancer [118]. Gold nanoparticles have been shown to enhance the efficacy of radiotherapy [119]. Thereby, when these particles reach hypoxic regions, this compensates the low anti-tumor efficacy of radiotherapy at tumor hypoxic sites. From an immunological perspective, _Salmonella_-induced changes in the immune component of tumor microenvironment could underlie its ability to enhance tumor radiosensitivity. [PERSON] et al. proposed various immunological mechanisms for radiosensitization, including: (a) increasing the number and activation levels of dendritic cells, (b) effective T-cell recruitment and activation, (c) inhibition of T-cell exhaustion and abrogation of inhibitory signaling, and (d) induction of specific cytokine (GM-CSF, IL-2 and IL-12) and chemokine (CCL3 and CCL5) release [120]. We have previously discussed the role of _Salmonella_ in manipulating both innate and adaptive components of the immune system and highlighted its potential in immunomodulating the tumor niche. The capacity of _Salmonella_ to transform the tumor microenvironment from being immunosuppressive to be immunogenic makes it a good candidate for improving the sensitivity of tumor to radiotherapy.