Engineered oncolytic bacteria have emerged as a promising therapeutic platform for precision cancer treatment, offering tumor-specific colonization, immune activation, and controllable therapeutic delivery. This review summarizes recent advances in the design and application of synthetic biological strategies that enhance bacterial precision, safety, and efficacy in tumor therapy. These strategies are categorized into three major regulatory modes: exogenous input–responsive gene circuits, autonomous bacterial signal–responsive gene circuits, and tumor microenvironment-responsive gene circuits.
Exogenous input–responsive gene circuits rely on external chemical molecules, light, temperature, or radiation to precisely regulate bacterial gene expression and therapeutic release, enabling spatiotemporally control of bacterial activity. These circuits provide several advantages: (1) precise temporal control over therapeutic delivery, (2) reduced metabolic burden during systemic circulation, and (3) enhanced safety through dose-dependent activation. Autonomous bacterial signal–responsive gene circuits employ quorum sensing, nitric oxide-responsive elements, or invasion/intracellular niche-responsive mechanisms to regulate gene expression in response to bacterial cues generated within tumors, ensuring coordinated therapeutic output within the tumor microenvironment. Tumor microenvironment-responsive gene circuits exploit intrinsic tumor characteristics, such as hypoxia, acidity, and elevated lactate levels, to activate bacterial functions selectively within tumors, thereby eliminating the need for external control and minimizing off-target effects.
In addition, the review discuss the current progress and challenges in translating engineered oncolytic bacteria into clinical practice, as well as future directions to further enhance their therapeutic potential. Beyond monotherapy, integrating engineered oncolytic bacteria with nanomedicine, immune checkpoint inhibitors, adoptive cell therapies, oncolytic viruses, or bacterial outer membrane vesicles have the potential to amplify antitumor responses and achieve synergistic therapeutic effects.
Overall, advances in synthetic biology have enabled the development of optimized oncolytic bacterial therapeutics, paving the way toward safe, effective, and personalized bacteria-based cancer therapies.

Key Findings
1. Three major induction strategies—exogenous input–responsive, autonomous bacterial signal–responsive, and tumor microenvironment-responsive gene circuits—enable precise regulation of bacterial gene expression and therapeutic activity within tumors.
2. Exogenous input–responsive gene circuits, activated by external small molecules, light, temperature, or radiation, offer controllable and reversible spatiotemporal regulation,, enhancing safety and flexibility.
3. Autonomous bacterial signal–responsive gene circuits leverage quorum sensing, nitric oxide-responsive elements, or invasion/intracellular niche-responsive mechanisms to achieve self-regulated, population-dependent therapeutic responses.
4. Tumor microenvironment–responsive gene circuits exploit tumor biomarkers such as hypoxia, acidity, and elevated lactate levels to ensure selective bacterial activation within tumor tissues.
5. Integration with other therapeutic modalities, including nanomedicine, immune checkpoint blockade, adoptive cell therapies, oncolytic viruses, and bacterial outer membrane vesicles— holds promise for advancing personalized and controllable cancer therapies.
This review summarizes recent advances in the engineering of oncolytic bacteria for precision cancer therapy, with a focus on externally signal-responsive, bacteria self- responsive, and tumor microenvironment-responsive bacterial systems.
DOI:10.1093/procel/pwaf085