From tumor targeting to tumor accessibility: surface-engineered bacteria as precision living therapeutics for translational medicine.

Abstract

The concept of bacterial therapy dates back over a century to clinical observations that incidental infections could induce tumor regression. Recent advances in genetic engineering and synthetic biology have since transformed bacteria into versatile living therapeutics with significant preclinical potential against diseases such as cancer, inflammatory disorders, and metabolic conditions. However, clinical translation faces considerable hurdles. Here, we provide a clinically oriented perspective on the translational gap in bacterial therapy. Drawing inspiration from the success of antibody-drug conjugates in achieving precise payload delivery, we highlight an emerging paradigm of "precision living therapeutics" enabled by bacterial surface engineering. we propose the concept of "Tumor accessibility" for the first time, and identify its insufficiency as a critical bottleneck in current therapeutic applications. We then systematically summarize recent advances in bacterial surface engineering, encompassing physical, chemical, and biological strategies, with a focus on their capacity to evade immune clearance, enhance tumor colonization, and improve therapeutic performance. Chemical approaches primarily involve covalent conjugation, including the SpyTag/SpyCatcher system and bioorthogonal click chemistry-based metabolic labeling. Physical strategies center on cell membrane encapsulation and surface coatings such as layer-by-layer encapsulation. Biological strategies include cell camouflage and genetic modulation of surface structures, display of functional biomolecules, and affinity-based systems such as biotin-streptavidin interactions. Finally, we discuss integrative strategies that combine surface-engineered bacteria with conventional treatment modalities, including physical therapy, chemotherapy, and immunotherapy. We propose that future clinical translation of bacterial therapy should shift from localized modification design to a holistic consideration of systemic accessibility.