Current status and future perspectives of multi-modal bacteria-based cancer therapies.

BACKGROUND: Targeted drug delivery systems have garnered increasing research interest in cancer threapy. Bacteria have emerged as a promising vehicle due to their innate ability to the tumour microenvironment (TME) and their intrinsic immune-stimulating properties. This review explores the application of bacteria in oncology, emphasizing the tumour-targeting behaviour of specific strains, their immunomodulatory functions, and their potential as delivery platforms for the controlled release of therapeutic agents. MAIN TEXT: This review synthesizes recent advances in bacteria-mediated cancer therapy, focusing on the mechanisms underlying bacterial targeting of hypoxic and immunosuppressive regions within the tumor microenvironment (TME). We discuss how genetic modification has been employed to design recombinant bacterial strains with enhanced tumor specificity and amplified therapeutic effects. Furthermore, the integration of bacteria with nanotechnology has facilitated the development of hybrid systems capable of targeted drug delivery and triggered-release mechanisms. The combination of bacterial therapy with other treatment modalities-such as photodynamic (PDT) and sonodynamic therapies (SDT)-is also examined, emphasizing their synergistic potential in overcoming tumor heterogeneity and enhancing anti-tumor immunity. Finally, we survey the current clinical progress of bacteria-based therapeutics and offer perspectives on the future role of artificial intelligence (AI) in improving the design and application of these living medicines. CONCLUSIONS: Bacteria-based delivery systems represent a multifunctional and innovative strategy in the evolution of targeted cancer therapies. Through genetic modification and nanobiotechnology approaches, bacteria can be customized to mediate multi-effect synergistic treatments for cancer, enhancing the precision, safety, and efficacy of cancer therapies. With the ongoing integration of advanced technologies, including AI, there is great potential to overcome existing limitations and accelerate the clinical translation of bacterial anticancer therapies. This interdisciplinary effort is poised to open new avenues for next-generation cancer treatments and lay the foundation for future directions in cancer research and therapeutic practice. KEY POINTS: Bacteria exhibit inherent tumour-targeting capabilities, particularly thriving in hypoxic tumour microenvironments (TMEs) and activating potent anti-tumour immune responses through pathogen-associated molecular patterns (PAMPs) and immunomodulation. Genetic engineering and nanobiotechnology enable advanced bacterial therapies, allowing for reduced toxicity, controlled proliferation, targeted drug delivery and the expression of therapeutic payloads (e.g., cytokines, enzymes, tumour antigens) within tumours. Bacteria serve as versatile platforms for multi-modal synergistic therapy, effectively combining with immunotherapy, photodynamic therapy (PDT), thermodynamic therapy (TDT), photothermal therapy (PTT) and sonodynamic therapy (SDT) to significantly enhance tumour eradication. Artificial intelligence (AI) is poised to revolutionise bacterial cancer therapy, offering powerful tools for optimising synthetic biology designs (e.g., promoters, gene circuits), nanocarrier engineering and predicting bacterial-host interactions for more effective and safer treatments.