From Passive Carriers to Niche Engineers: The Evolving Paradigm of Engineered Bacteria in Cancer Therapy

Engineered bacterial systems have been predominantly conceptualized as living drug-delivery vehicles, with their therapeutic value attributed primarily to tumor-homing capabilities and payload delivery. This framing, while productive in guiding early-stage research, may inadvertently constrain both the design space and the therapeutic ambition of bacterial therapeutics. An alternative perspective is emerging from recent advances in synthetic biology and tumor immunology: bacteria may be understood not merely as passive carriers of therapeutic payloads but as active participants in the remodeling of the tumor ecosystem. This review examines the conceptual and empirical foundations of this paradigm shift, tracing the evolution from bacteria as delivery vehicles to bacteria as “niche engineers” capable of metabolic reprogramming, immunological modulation, and structural reorganization of the tumor microenvironment. The discussion progresses through four interconnected dimensions—colonization, remodeling, orchestration, and adaptation—each of which redefines the bacterium’s functional role in the therapeutic context. Critically, the review engages with unresolved mechanistic questions that complicate the therapeutic narrative, including the dual role of IL-10 in both sustaining bacterial persistence and suppressing antitumor immunity, the spatial heterogeneity of bacterial colonization and its implications for therapeutic efficacy, and the evolutionary pressures that may select for loss-of-function mutants. The clinical translation landscape is examined with attention to manufacturing challenges, regulatory uncertainties, and the potential failure modes of combination strategies. By situating engineered bacteria within the broader ecological dynamics of the tumor microenvironment, this review aims to provide a framework for the next generation of bacterial therapeutics that engage more fully with the complexity of cancer as a systemic disease.