# Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment
## 1 Introduction  
Conventional anti-cancer therapy generally involves the use of surgery, chemical chemotherapeutic agents, and radiation therapy. However, a major problem when using conventional anti-cancer therapeutics is non-specific toxicity to normal cells and poor penetration into tumor cells. Moreover, prolonged usage of chemotherapeutics has led to the development of drug resistance resulting in ineffective treatment. This has served as a driving force for the development of alternative anti-tumor therapeutics [1]. Vaccines, in the form of attenuated bacteria and viruses, have been used to provide immunity against pathogenic infections and are now being investigated for anti-tumor properties to widen the scope of novel anti-cancer therapeutics.  
The advent of microbial therapy for cancer treatment was first reported in 1867, by a German physician Dr. [PERSON], who highlighted a case of cancer remission when the patient contracted ersispelas (now known as _Streptococcus pyogenes_) [2]. In the late 19 th century, Dr. [PERSON], a surgeon at the New York Hospital observed regression in tumors after the patients developed skin infection due to Streptococcus bacteria. Dr. [PERSON] posited the hypothesis that these infections stimulated the immune system to curb the tumor growth. He then started injecting the patients with live cultures of _Streptococcus_ to inspect the tumor regression, however, some fatalities were observed. In response to this, [PERSON] administered mixture of lysates obtained from _Streptococcus pyogenes_ and heat-killed _Serratio marcescens_, commonly termed as [PERSON]'s toxin which is considered as the firstexample of cancer immunotherapy [3, 4]. The serendipitous benefit of concurrent infection due to the presence of pathogenic bacteria in tumors led to the investigation of bacterial activity against cancer.  
The motility of bacteria is responsible for swimming in the vasculature and effective penetration into tumors. Bacterial infections activate the innate and adaptive immune system which not only targets the bacteria but also, tumor cells. This ability of the bacteria has been used to develop bacterial anti-cancer therapy. An essential step in the development of bacterial therapeutics is the identification of potential species and strains of bacteria possessing minimal pathogenicity to the host [5]. An ideal anti-cancer bacterium should be: (i) non-toxic and non-immunogenic to the host, (ii) should replicate only in the tumor, (iii) spread evenly throughout it, and (iv) cause lysis of the tumor cells [6]. The hypoxic environment of the tumor tissue is suitable for colonization and supports the growth of bacteria (known as tissue tropism). For instance, anaerobic bacteria such as _Clostridia_ species, have the tendency to preferentially accumulate and grow in tumors rather than normal cells due to the conducive tumor environment. This favors anaerobic growth of bacteria and offers protection from the host immune system [7]. In addition, competition for essential nutrients between bacteria and tumor cells may also result in anti-tumor effect.  
In this review, we aim to introduce and summarize bacterial-based anti-cancer approaches. Genetic engineering and synthetic biology are essential tools to bioengineer therapeutic bacteria to maximize their efficiency in cancer treatment. Bacteria can be genetically engineered and used as direct oncolytic agents or as vectors for delivery of gene therapy, cytotoxic agents, and peptides [8, 9, 10]. Species of _Clostridia_, _Bifidobacteria_, and _Salmonellae_ are commonly used as vectors for delivery of tumor suppressor genes, tumor associated antigens, or suicide genes [8]. The use of bacterial anti-cancer therapy in conjunction with the conventional cancer therapy as effective treatment options have also been described.