The research community has achieved a growing ability to engineer bacteria to produce specific behaviors and outcomes. In the realm of cancer therapy, this includes altering the characteristics of bacteria to increase their ability to disrupt cancer cells by preferentially localizing to and colonizing tumor tissue. Techniques demonstrated in the laboratory include genetic engineering of bacteria manufacture or carry a payload of molecules capable of directly harming cancerous cells. The review noted here outlines the range of present approaches, including those that are progressing towards clinical use.
In contrast to conventional drugs, which accumulate through passive diffusion, live bacteria can actively penetrate deep into tumors, bypassing aggregation near blood vessels. The unique properties of the tumor microenvironment (TME) allow bacteria to preferentially replicate and colonize tumors. For example, Salmonella has been observed to localize to tumors at more than 10,000 times the density found in normal tissues. Live bacteria offer distinct advantages over traditional anticancer agents by amplifying antitumor effects through inherent tumor-targeting capabilities, potentially enhancing specific immune recognition. However, balancing the requirement for bacteria to evade host antimicrobial defenses while stimulating antitumor immunity within the TME remains a challenge.
Advances in synthetic biology allow the rational design of optimized oncolytic bacterial strains by attenuating virulence factors and integrating customizable therapeutic payloads, with several candidates already progressing into clinical evaluation. Fine-tuning the spatiotemporal control of bacterial therapeutic activity is essential for maximizing drug accumulation, improving resource efficiency, and reducing harm to healthy tissues. To this end, engineered oncolytic bacteria often utilize regulated gene expression systems, incorporating specific promoter elements, to allow for precise control of therapeutic payload delivery in vivo. Synthetic biology prioritizes rational and modular design, integrating programmable sensors, genetic circuits, and effectors to deliver precise, tunable, multilayer regulation of bacterial behaviors and therapeutic outputs.
Link: https://doi.org/10.1093/procel/pwaf085
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