From Mechanism to Clinic: Engineered Bacteria-Nanomaterial Hybrid Systems for Cancer Immunotherapy.

Hypoxia, immunosuppression, and pronounced heterogeneity within the tumor microenvironment (TME) hinder the effectiveness of cancer therapies. Engineered bacteria-nanomaterial hybrid systems have emerged as a promising approach to address these challenges. Bacterial chassis provide active tumor targeting, deep tissue penetration, and in situ proliferation, facilitating the precise delivery of immunomodulators. Concurrently, nanomaterials interfaced with these living carriers can be activated by external physical stimuli, inducing photothermal, photodynamic, sonodynamic, and magnetothermal effects within solid tumors. These interactions promote immunogenic cell death (ICD) and enable real-time monitoring. Recent advances in synthetic biology and nanotechnology have led to the development of an expanding range of preclinical biohybrid platforms, while several related components, including bacterial therapeutics, bacterial derivatives, and physically activated nanomedicine platforms, have progressed into clinical evaluation. This review first explores the origins and roles of tumor-associated bacteria. It then summarizes strategies for engineering bacteria-nanomaterial hybrid systems. Subsequently, this review examines how physical stimuli enhance targeting, remodel the TME, and amplify antitumor immunity. Finally, safety, manufacturing, and regulatory challenges impacting clinical translation are discussed. Overall, these platforms offer a potentially powerful framework for precision cancer immunotherapy. However, successful clinical translation will require stronger evidence regarding safety, controllability, manufacturing consistency, and therapeutic efficacy.