Hacking the Immune Response to Solid Tumors: Harnessing the Anti-Cancer Capacities of Oncolytic Bacteria

Abstract

Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, Salmonella, and Clostridium. Advancements in techniques and methodology, including genetic engineering, create opportunities to “hijack” typical host–pathogen interactions and subsequently harness oncolytic capacities. Engineering, sometimes termed “domestication”, of oncolytic bacterial species is especially beneficial when solid tumors are inaccessible or metastasize early in development. This review examines reported oncolytic bacteria–host immune interactions and details the known mechanisms of these interactions to the protein level. A synopsis of the presented membrane surface molecules that elicit particularly promising oncolytic capacities is paired with the stimulated localized and systemic immunogenic effects. In addition, oncolytic bacterial progression toward clinical translation through engineering efforts are discussed, with thorough attention given to strains that have accomplished Phase III clinical trial initiation. In addition to therapeutic mitigation after the tumor has formed, some bacterial species, referred to as “prophylactic”, may even be able to prevent or “derail” tumor formation through anti-inflammatory capabilities. These promising species and their particularly favorable characteristics are summarized as well. A complete understanding of the bacteria–host interaction will likely be necessary to assess anti-cancer capacities and unlock the full cancer therapeutic potential of oncolytic bacteria.

Toward Practical Applications of Engineered Living Materials with Advanced Fabrication Techniques

“…The primary goal of applying ELMs in cancer therapy is to develop engineered bacteria that can specifically target tumor sites to release therapeutic agents and kill cancer cells. These bacteria can be genetically modified to carry antitumoral agents or promote therapeutic effects, including cytotoxic agents, 116 immune modulators, 117 cytokines, 117 prodrug-converting enzymes, 118 small interfering RNA, 119 and nanobodies. 120 Recent research highlights the potential of both wild and engineered bacteria for targeted tumor therapy.…”

“…118 Additionally, some oncolytic bacteria can produce antitumor molecules and regulate the immune system to promote the entry of macrophages and dendritic cells into tumors, inhibiting their progression. 116 Edible yeast expressing mannose, which binds to the mannose receptor of tumorassociated macrophages in the tumor microenvironment, can be used for targeted delivery. 121,122 These natural or wild living organisms with anticancer effects serve as excellent candidates for developing anticancer agents.…”

“…For instance, engineered E. coli can specifically bind to glycosaminoglycan proteins on colorectal cancer cells and secrete myrosinase enzymes, converting glucosinolates from food into anticancer active small molecules like sulforaphane, thereby reducing cancer incidence . Additionally, some oncolytic bacteria can produce antitumor molecules and regulate the immune system to promote the entry of macrophages and dendritic cells into tumors, inhibiting their progression . Edible yeast expressing mannose, which binds to the mannose receptor of tumor-associated macrophages in the tumor microenvironment, can be used for targeted delivery. , These natural or wild living organisms with anticancer effects serve as excellent candidates for developing anticancer agents.…”