Bacteria mediated tumor therapy recent advances challenges and future perspectives

Bacteria, as simple unicellular microorganisms, can directly lyse tumor cells following intratumoral administration. Flagellin and cell wall components derived from bacteria can reshape the tumor microenvironment and activate host anti-tumor immune responses. Notably, certain anaerobic and facultative anaerobic bacteria exhibits preferential colonization in the hypoxic core of solid tumors, where they can serve as in situ "micro-bioreactors" and targeted delivery vectors for synergistic tumor therapy. Based on rapid advances in synthetic biology, diverse engineered bacteria and bacteria-based biohybrid systems have been developed for precision tumor therapy, including gene restoration, environment-responsive programmable expression, cytotoxic protein production, and multimodal combination therapy with nanomaterials, immune modulators, or photothermal agents. These living platforms enable targeted drug/gene delivery, sustained local therapeutic output, and durable anti-tumor immune activation. However, clinical translation remains hindered by insufficient biosafety control, off-target colonization, uncontrolled proliferation, immune clearance, and lack of standardized manufacturing and regulatory guidelines. This review systematically summarizes the historical development, inherent anti-tumor mechanisms, genetic engineering strategies, and multimodal biohybrid systems of bacteria-mediated tumor therapy. We comprehensively discuss the advantages, limitations, comparative characteristics, and core bottlenecks of different platforms, and propose rational design strategies for next-generation intelligent, controllable, and clinically translatable bacteria-derived living anti-tumor systems.