Synthetic biology strategies for engineering bacteriophages against intracellular tumor-associated bacteria: emerging tools for precision oncology

The tumor microenvironment (TME) comprises malignant, stromal, immune, and microbial components. Spatial imaging and molecular profiling have identified intracellular bacteria or bacterial signals in selected tumors, although localization, viability, and functional significance vary across tumor types and experimental settings. Certain tumor-associated bacteria can influence cancer progression and treatment response, motivating strategies for selective microbial intervention. Bacteriophages offer bacterial specificity and opportunities for engineering, but their access to intracellular targets remains a major challenge. This narrative review examines three proposed strategies: lytic elimination of intracellular bacteria, modification of bacterial functions, and bacterial production of therapeutic payloads following phage-mediated delivery. Evidence from mammalian-cell uptake studies, intracellular infection models, and emerging cancer cell-bacterium co-cultures supports individual components of these strategies. However, the complete sequence linking systemic engineered phage delivery, intracellular bacterial clearance, and antitumor immune reprogramming has not been established in orthotopic tumor models or human tumor organoid systems. We therefore present the intracellular scalpel as a testable hypothesis and discuss its potential combinations with established cancer treatments and exploratory adjuvants. Particular attention is given to delivery barriers, evidence limitations, biosafety, and the preclinical measurements required to determine whether intracellular bacterial targeting can improve cancer treatment.