Bacteria-cancer interactions: bacteria-based cancer therapy

Abstract

Recent advances in cancer therapeutics, such as targeted therapy and immunotherapy, have raised the hope for cures for many cancer types. However, there are still ongoing challenges to the pursuit of novel therapeutic approaches, including high toxicity to normal tissue and cells, difficulties in treating deep tumor tissue, and the possibility of drug resistance in tumor cells. The use of live tumor-targeting bacteria provides a unique therapeutic option that meets these challenges. Compared with most other therapeutics, tumor-targeting bacteria have versatile capabilities for suppressing cancer. Bacteria preferentially accumulate and proliferate within tumors, where they can initiate antitumor immune responses. Bacteria can be further programmed via simple genetic manipulation or sophisticated synthetic bioengineering to produce and deliver anticancer agents based on clinical needs. Therapeutic approaches using live tumor-targeting bacteria can be applied either as a monotherapy or in combination with other anticancer therapies to achieve better clinical outcomes. In this review, we introduce and summarize the potential benefits and challenges of this anticancer approach. We further discuss how live bacteria interact with tumor microenvironments to induce tumor regression. We also provide examples of different methods for engineering bacteria to improve efficacy and safety. Finally, we introduce past and ongoing clinical trials involving tumor-targeting bacteria.

Fig. 1. Mechanisms by which bacteria target tumors.

After systemic administration, bacteria localize to the tumor microenvironment. The interactions between bacteria, cancer cells, and the surrounding microenvironment cause various alterations in tumor-infiltrating immune cells, cytokines, and chemokines, which further facilitate tumor regression. ① Bacterial toxins from S. Typhimurium, Listeria, and Clostridium can kill tumor cells directly by inducing apoptosis or autophagy^,,–,. Toxins delivered via Salmonella can upregulate Connexin 43 (Cx43), leading to bacteria-induced gap junctions between the tumor and dendritic cells (DCs), which allow cross-presentation of tumor antigens to the DCs^–. ② Upon exposure to tumor antigens and interaction with bacterial components, DCs secrete robust amounts of the proinflammatory cytokine IL-1β, which subsequently activates CD8⁺ T cells^,. ③ The antitumor response of the activated CD8⁺ T cells is further enhanced by bacterial flagellin (a protein subunit of the bacterial flagellum) via TLR5 activation. The perforin and granzyme proteins secreted by activated CD8⁺ T cells efficiently kill tumor cells in primary and metastatic tumors^,. ④ Flagellin and TLR5 signaling also decreases the abundance of CD4⁺ CD25⁺ regulatory T (T_reg) cells, which subsequently improves the antitumor response of the activated CD8⁺ T cells. ⑤ S. Typhimurium flagellin stimulates NK cells to produce interferon-γ (IFN-γ), an important cytokine for both innate and adaptive immunity. ⑥ Listeria-infected MDSCs shift into an immune-stimulating phenotype characterized by increased IL-12 production, which further enhances the CD8⁺ T and NK cell responses. ⑦ Both S. Typhimurium and Clostridium infection can stimulate significant neutrophil accumulation^,,,. Elevated secretion of TNF-α^, and TNF-related apoptosis-inducing ligand (TRAIL) by neutrophils enhances the immune response and kills tumor cells by inducing apoptosis. ⑧ The macrophage inflammasome is activated through contact with bacterial components (LPS and flagellin) and Salmonella-damaged cancer cells, leading to elevated secretion of IL-1β and TNF-α into the tumor microenvironment^,. NK cell: natural killer cell. T_reg cell: regulatory T cell. MDSCs: myeloid-derived suppressor cells. P2X₇ receptor: purinoceptor 7-extracellular ATP receptor. LPS: lipopolysaccharide