Engineering bacteria for enhanced tumor therapy: from surface modification to synthetic genetic circuits.

Bacterial therapy represents a promising strategy for cancer treatment, in which tumor regression can be achieved through bacteria-mediated immunotherapy. The mechanisms involve disrupting cellular metabolism, inducing apoptosis, delivering therapeutic agents, and enhancing anticancer immune responses. Naturally occurring bacteria possess inherent advantages in biocompatibility and self-propulsion. Facultative anaerobic species, such as Salmonella, can increase tumor accumulation by more than tenfold through the enhanced permeability and retention (EPR) effect. However, the application of native bacterial therapy is limited by its toxicity and unstable colonization in vivo at disease sites. The negatively charged bacterial surface and abundant functional groups enable surface modifications through ionic interactions or covalent bonding. These approaches include modifying lipopolysaccharides and capsules that trigger in vivo toxicity, or coating bacteria with exogenous nanomaterials to achieve detoxification and construct drug delivery platforms. Furthermore, gene editing and synthetic genetic circuit strategies allow the precise engineering of bacteria to improve tumor targeting, reduce pathogenicity, and endow them with novel anticancer functions. This review discusses the routes of bacterial administration, surface engineering strategies, synthetic circuit design, and clinical translation in bacteria-mediated cancer immunotherapy. It comprehensively summarizes the historical progress, advantages, and distinctive features of bacterial therapy, with a particular emphasis on recent advances in synthetic gene circuit design. Finally, the review highlights the clinical translation prospects and existing challenges of bacteria-mediated tumor therapy, aiming to ensure biosafety, prevent unintended immune responses, and promote large-scale clinical applications in cancer treatment.