Resynthesis of synthetic biology techniques: combining engineered bacteria with other antitumour therapies

Abstract

Worldwide cancer mortality rates underscore the pressing need to identify and develop novel anticancer therapies to supplement traditional cancer treatments. Naturally occurring bacteria are ideal for cancer therapy owing to their autonomous propulsion and hypoxia-targeting properties, but their poor tumour targeting ability and weak tumour penetration limit their use. Bacteria can be modified by bioengineering and nanotechnology methods to improve their physiological activity and therapeutic effect. Furthermore, engineering allows for refined spatiotemporal control, precise functional recombination, and direct genetic reprogramming. These engineered bacteria can produce synergistic anticancer effects upon coadministration with anticancer drug-containing nanomaterials or other therapeutic payloads. In this paper, the use of engineered bacteria combined with other antitumour therapies, such as radiotherapy (RT), chemotherapy, immunotherapy, light therapy and life technology, is reviewed to aid in improving antitumour therapy efficacy. In addition, we provide an overview of the current state of spatiotemporally regulated bacterial gene expression and drug release, discuss the drawbacks and difficulties of employing engineered bacteria for tumour therapy, and explore potential research avenues on the basis of current advancements.

Keywords: antitumour therapy; engineered bacteria; spatiotemporal manipulation; synthetic biology; therapeutic effect.

Figure 1

Combination therapy with engineered bacteria and other therapies. (a) Combining engineered bacteria with radiotherapy can alleviate intratumor hypoxia and increase tumour radiosensitivity to activate immunity. (b) Engineered bacteria combined with chemotherapy can be used to configure drug nanocarriers via synthetic biology techniques. (c) Throughout each phase of the biological reaction, bacteria can generate payloads to interact with specific immune cells, enabling more effective reprogramming of the antitumour response. (d) The surfaces of bacteria can be modified with appropriate photothermal and photosensitisers that are converted into thermal energy (PTT) or produce singlet oxygen (PDT) when illuminated by light without compromising their ability to target tumours or even further stimulate immune responses. (e) Combined engineered bacteria can carry or increase the replication of oncolytic viruses; thus, they are more conducive to combined treatment with oncolytic viruses. (f) Administration of engineered bacteria combined with CAR-T-cell therapy can be activated by bacterial adjuvants and respond to synthetic antigens released by bacteria. (g and h) The synthesised bacterial complex can interact with microorganisms in the human body (especially in the intestines) and intratumoral bacteria to promote predictable immune responses or decrease the number of germs that cause cancer.

Figure 2

Engineered bacteria and immunotherapy. Immunogenic single-agent bacteria can change the TME by binding to TLR-4 and TLR-5, which are activated by flagella and lipopolysaccharide, respectively. As a result, the native macrophage phenotype changes, and innate immune cells such as neutrophils, monocytes, and NK cells infiltrate the tumour. Bacteria are phagocytosed as immune cells move into the malignant region, providing a chance to transfer immune cell-specific cargo intracellularly. As a result, STING agonists can be delivered to intratumoural APCs by E. coli, triggering IFN-I reactions. By generating immunomodulators (such as cytokines and chemokines) to attract tumour-infiltrating lymphocytes to the tumour area, bacteria can engage with the host’s adaptive immune system.

Figure 3

The spatiotemporal manipulation of engineered bacteria. (A) Spatiotemporal manipulation by light; (B) spatiotemporal manipulation by a magnetic field; (C) spatiotemporal manipulation by an acoustic wave. (D) Spatiotemporal manipulation by HBO. Created in BioRender. Chang (2025): https://BioRender.com/1ao7wx5.