Path to bacteriotherapy: From bacterial engineering to therapeutic perspectives.

The major reason for the failure of conventional therapies is the heterogeneity and complexity of tumor microenvironments (TMEs). Many malignant tumors reprogram their surface antigens to evade the immune surveillance, leading to reduced antigen-presenting cells and hindered T-cell activation. Bacteria-mediated cancer immunotherapy has been extensively investigated in recent years. Scientists have ingeniously modified bacteria using synthetic biology and nanotechnology to enhance their biosafety with high tumor specificity, resulting in robust anticancer immune responses. To enhance the antitumor efficacy, therapeutic proteins, cytokines, nanoparticles, and chemotherapeutic drugs have been efficiently delivered using engineered bacteria. This review provides a comprehensive understanding of oncolytic bacterial therapies, covering bacterial design and the intricate interactions within TMEs. Additionally, it offers an in-depth comparison of the current techniques used for bacterial modification, both internally and externally, to maximize their therapeutic effectiveness. Finally, we outlined the challenges and opportunities ahead in the clinical application of oncolytic bacterial therapies.