From pathogen to “living drug factory” innovative strategies and clinical translation of bacteria as programmable intelligent vectors for cancer therapy

Abstract The dynamic interplay between intratumoral bacteria and cancer progression has unveiled new avenues for precision oncology, positioning bacteria as versatile, programmable platforms for targeted therapy. This review systematically explores the dual roles of tumor‐associated microbiota‐both promoting and suppressing malignancy‐and highlights the transformative potential of engineered bacterial systems in cancer treatment. Capitalizing on their innate tropism for hypoxic tumor cores, bacteria serve as self‐propelled, living drug carriers capable of localized delivery of cytotoxic agents, immunomodulators, and prodrug‐converting enzymes. Advances in synthetic biology and nano‐biohybrid designs have further enabled the development of intelligent bacterial vectors that respond to tumor‐specific signals, thereby minimizing off‐target effects and enhancing therapeutic precision. We discuss innovative strategies in which bacteria are harnessed to remodel the immunosuppressive tumor microenvironment (TME), potentiate immune checkpoint therapies, and synergize with conventional modalities such as chemotherapy, radiotherapy, and photodynamic therapy. Emphasis is placed on bacterial‐derived components‐including outer membrane vesicles, spores, and metabolites‐that can be functionally repurposed for cancer immunotherapy and targeted drug delivery. Furthermore, we examine ongoing clinical trials that underscore the translational feasibility of bacterial therapeutics, while also addressing persistent challenges in safety, biocontainment, and manufacturing scalability. Looking forward, we envision a new paradigm in which engineered bacteria, integrated with real‐time imaging and personalized microbiome profiling, evolve from experimental tools into clinically deployable “living medicines.” By bridging synthetic biology, immunology, and materials science, bacteria‐based platforms offer a promising frontier for achieving potent, specific, and adaptable cancer therapies.