Bioengineering of bacteria for cancer immunotherapy

Abstract

Here, we provide a brief overview of the approaches and strategies underlying bacteria-based cancer immunotherapy (BCiT). We also describe and summarize research in the field of synthetic biology, which aims to regulate bacterial growth and gene expression for immunotherapeutic use. Finally, we discuss the current clinical status and limitations of BCiT.

Fig. 1. Engineered bacteria-based cancer immunotherapy.

a, b In the presence of chemical molecules such as Doxy or l-arabinose, bacteria secrete ClyA to kill cancer cells, or FlaB to reprogram the TME, to increase recruitment of antitumor M1-like macrophages through TLR-4 and TLR-5 signaling^,,. c Other potential approaches include physical factors such as light, heat, or focused ultrasound, which can be used to stimulate bacteria to deliver immunotherapeutics into the TME^,,,,,. d, e Bacteria have been genetically modified with the QS system, which in this case is based on the AHL autoinducer. In this system, AHL is produced via the luxI promoter and controlled expression of lysE, resulting in quorum-mediated lysis and intratumoral release of drugs such as CD47-blocking nanobodies or PD-L1- and CTLA-4-blocking nanobodies. Reproduced with permission from ref. , reprinted with permission from Springer Nature, ref. , and the American Association for the Advancement of Science (AAAS). f Tumor-infiltrating T cells stimulated by cleaved neoantigens detect and kill tumor cells. Reprinted with permission from ref. (copyright 2021, American Chemical Society). g, h Engineered bacteria can also stimulate adaptive immune responses against tumors by secreting cytokines, chemokines, or other immunomodulatory cargoes to recruit and activate TILs in the TME^,,. Reproduced with permission from ref. and reprinted with permission from Springer Nature. The image was created using BioRender.com.