Spontaneous tumor regression, defined as “the partial or complete disappearance of a malignant tumor in the absence of treatment or in the presence of therapy considered inadequate to exert a significant influence on the disease,” is a phenomenon that has been observed over the past several hundred years. Interestingly, several of these cases report concurrent infections such as hepatitis, malaria, measles, smallpox, and tuberculosis, amongst others.1 In 1891, an orthopedic surgeon uncovered such a case involving a patient with a large recurrent sarcoma that became infected with Streptococcus pyogenes. Following infection, the patient developed a fever and the tumor began to shrink in size before disappearing completely. Suspecting the infection to be the cause of such a drastic turnabout, William Coley devised what would become known as “Coley’s toxins,” a treatment containing two heat-killed bacteria, Streptococcus pyogenes and Serratia marcescens, as a new form of cancer therapy.1 His methods were met with mixed success—many patients saw tumor regression and even complete clearance in some cases. Unfortunately, the rate of infection and side effects of this therapy were difficult to control, and at the time, radiotherapy and chemotherapy had become established methods of cancer treatment that were easily standardized in comparison to Coley’s approach.2 Fast forward to today, scientific advances have allowed for the usage of reprogrammed bacteria in a similar manner. In the face of tumors that utilize sophisticated techniques to evade the immune system, researchers enlist the aid of tiny soldiers whose use can seem counterintuitive. Although they may go largely unnoticed, microorganisms such as bacteria are everywhere: in the air, on the ground, and of course, in people. The human body is home to bacteria that can aid in normal physiological processes and reside in areas such as the skin, the digestive system, and the respiratory system. Nonetheless, bacteria is often considered pathogenic, a cause for disease rather than a cure for one. Interestingly enough, its infectious properties are precisely what make bacteria effective against cancer, which is difficult to treat in part due to issues associated with targeting malignant cells. Cancer cells are constantly evolving and are able to develop resistance to new drug treatments. Again, because cancer is dynamic, tumors often display heterogeneity and are able to evade the host immune system or even utilize it to proliferate.3 This is where bacteria come in. Tumors can use a variety of mechanisms to suppress the local immune system, and as a result, the body often has difficulty attacking these biological “blind spots.” However, this is no problem for bacteria, which are moreso able to infect these areas because of the body’s lowered defenses. In fact, the hypoxic and anoxic microenvironments of tumors are great conditions in which to harbor bacteria, resulting in at least a thousand-fold increase of bacteria in these sites compared to in normal tissue.4 Following infection, the microbes naturally elicit the body’s immune response and serve as a homing device for tumor destruction. Essentially, this method supplements the abilities of the innate immune system and lends it a pair of glasses. The once “invisible” cells are now marked for destruction, and although our allies, the bacteria, are destroyed in the process, they take the tumor cells with them. Of course, upon entry into the body, the bacteria may very well attack healthy tissues if it is not administered in careful doses or some under some other form of control. Keeping this in mind, researchers at the Chonnam National University Hwasun Hospital engineered a strain of Salmonella typhimurium, a common cause of food poisoning, to secrete a bacterial flagellin, FlaB, that activates innate immune responses via a Toll-like receptor signaling pathway. In order to control the rate of infection and minimize side effects from systemic bacterial toxicity, a promoter inducible by L-arabinose was incorporated into the strain. The presence or absence of this food source allows researchers to control the timing of gene expression and subsequent bacterial proliferation. Given time to clear from the liver and spleen, where it tends to accumulate initially, the bacteria was able concentrate at the tumor sites after a period of 3 days post infection. Absence of serious inflammation or sepsis upon FlaB induction indicated that the engineered bacteria were able to successfully localize at the tumors. When this treatment was intravenously injected into the tails of mice with colon cancer, researchers observed significant growth inhibition of the primary tumor, with complete tumor regression in 55% of the mice 24 days post infection.4 With the power of an entire army of microscopic soldiers now in hand, bacteria-aided treatment provides a possible alternative to several conventional cancer therapies. The immune system is able to benefit from bacterial assistance against malignant cells without experiencing the immunosuppression that often occurs during chemotherapy. Surgical recession of tumors is a common practice but may disrupt malignant cells and place patients at risk for metastasis, a dangerous situation in which portions of the primary tumor break away and spread to other parts of the body. Taking advantage of qualities inherent to all tumor types, bacteria is able to target these malignant tissues nonspecifically, rendering it effective against these metastases, which are often aggressive tumors that have lost their identifiable markers and become undifferentiated. Other researchers have taken a slightly different approach toward using bacteria to combat cancer. Working to target metastatic tissues, they reprogrammed strains of bacteria and utilized them as vehicles for targeted drug delivery, again relying on the tendency of bacteria to aggregate at tumor sites. Taking advantage of immunosuppression in the pancreatic tumor microenvironment, researchers at Albert Einstein College of Medicine coupled radioactive isotope 188rhenium to Listeria monocytogenes, a strain of bacteria also known for causing food poisoning. Although radionuclide therapy has been largely successful in the treatment of several types of cancer, it has been markedly less effective in treating pancreatic cancer. However, this method of delivery that allows for concentrated drug activity resulted in a 90% decrease in the number of metastases.5 Similarly, scientists at MIT incorporated artificial genetic circuits into E. coli that allow the bacteria to destroy malignant cells by releasing membrane-dissolving hemolysin, inducing apoptosis, and encouraging host immune response. Combined with chemotherapy drug 5-fluorouracil, they saw dramatic decrease in tumor size in their mouse colon cancer model.6 Here researchers seem to combine the two previous methods to not only supplement our innate immune system, but perhaps to create a distinct system to combat disease separate from our own. Although they appear promising, innovative systems such as these are not wholly without risks. Researchers have certainly been able to manipulate several of the important aspects of bacterial function in regards to their use in cancer treatment; however, it remains a question as to whether we will able to fully control these microorganisms. Living organisms are unpredictable, as are their interactions with other living organisms. Moving forward, we must consider the long-term effects of these modified organisms in the human body and even their interactions with other bacteria inhabiting our bodies. As it stands, we do not boast the best track record with bacteria—the effect of antibiotic resistance has created various drug-resistant strains that have become an emerging concern in public health. Nonetheless, for those who have failed to see improvement with conventional cancer therapy, the potential benefits of bacteria-based treatments may outweigh the fact that we may never fully curb the inherent dangers of working with these modified organisms. More and more as we approach uncharted territory, it becomes clear that bacteria-based therapies may become a double-edged sword, and that only time will tell whether it has more potential to do harm or good. REFERENCES Jessy, Thomas. “Immunity over Inability: The Spontaneous Regression of Cancer.” Journal of Natural Science, Biology, and Medicine 2.1 (2011): 43–49. PMC. Web. 8 Mar. 2017. Felgner, Sebastian et al. “Bacteria in Cancer Therapy: Renaissance of an Old Concept.” International Journal of Microbiology 2016 (2016): 8451728. PMC. Web. 8 Mar. 2017. Chakraborty, Sajib, and Taibur Rahman. “The Difficulties in Cancer Treatment.” ecancermedicalscience 6 (2012): ed16. PMC. Web. 8 Mar. 2017. Zheng, Jin Hai et al. “Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin.” Science Translational Medicine 9.376 (2017). STM. Web. 8 Mar. 2017. Quispe-Tintaya, Wilber et al. “Nontoxic Radioactive Listeriaat Is a Highly Effective Therapy against Metastatic Pancreatic Cancer.” Proceedings of the National Academy of Sciences of the United States of America 110.21 (2013): 8668–8673. PMC. Web. 8 Mar. 2017. Din, M. Omar et al. “Synchronized Cycles of Bacterial Lysis for in Vivo Delivery.” Nature 536.7614 (2016): 81–85. PMC. Web. 8 Mar. 2017.