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\u00a0in 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\u00a0modes: exogenous input\u2013responsive gene circuits, autonomous bacterial signal\u2013responsive gene circuits, and tumor microenvironment-responsive gene circuits.<\/p>\n
Exogenous input\u2013responsive gene circuits rely on external chemical molecules, light, temperature, or radiation\u00a0to precisely regulate bacterial gene expression and therapeutic release, enabling\u00a0spatiotemporally 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\u00a0dose-dependent\u00a0activation.<\/p>\n
Autonomous bacterial signal\u2013responsive gene circuits employ\u00a0quorum sensing, nitric oxide-responsive elements, or invasion\/intracellular niche-responsive mechanisms\u00a0to regulate gene expression\u00a0in response to bacterial\u00a0cues generated within tumors, ensuring coordinated therapeutic output within the tumor microenvironment. Tumor microenvironment-responsive gene circuits exploit intrinsic tumor characteristics, such as\u00a0hypoxia, acidity, and elevated lactate\u00a0levels, to\u00a0activate bacterial functions selectively within tumors, thereby eliminating the need for external control and minimizing off-target effects.<\/p>\n
In addition, the review\u00a0discuss the current progress and challenges in translating engineered oncolytic bacteria into clinical practice, as well as future directions to\u00a0further\u00a0enhance their therapeutic potential. Beyond monotherapy, integrating engineered oncolytic bacteria with nanomedicine, immune checkpoint inhibitors, adoptive cell therapies, oncolytic viruses, or\u00a0bacterial outer membrane vesicles have the potential to amplify antitumor responses and achieve synergistic therapeutic effects.<\/p>\n
Overall, advances in synthetic biology have enabled the development of optimized oncolytic bacterial therapeutics, paving the way\u00a0toward safe, effective, and personalized bacteria-based cancer therapies.<\/p>\n
Key findings<\/p>\n
1.\u00a0Three major induction strategies-exogenous input\u2013responsive, autonomous bacterial signal\u2013responsive, and tumor microenvironment-responsive gene circuits-enable precise regulation of bacterial gene expression and therapeutic activity\u00a0within tumors.<\/p>\n
2. Exogenous input\u2013responsive gene circuits, activated by\u00a0external small\u00a0molecules, light, temperature, or radiation, offer controllable and reversible spatiotemporal regulation,, enhancing safety and flexibility.<\/p>\n
3. Autonomous bacterial signal\u2013responsive gene circuits\u00a0leverage quorum sensing, nitric oxide-responsive elements, or invasion\/intracellular niche-responsive mechanisms\u00a0to achieve self-regulated, population-dependent therapeutic responses.<\/p>\n
4. Tumor microenvironment\u2013responsive gene circuits\u00a0exploit tumor biomarkers such as hypoxia, acidity, and elevated lactate levels to ensure selective bacterial activation within tumor\u00a0tissues.<\/p>\n
5. Integration with other therapeutic modalities,\u00a0including nanomedicine, immune checkpoint blockade, adoptive cell therapies, oncolytic viruses, and bacterial outer membrane vesicles-\u00a0holds promise for\u00a0advancing personalized and controllable cancer therapies.<\/p>\n
This review summarizes recent advances in the engineering of oncolytic bacteria for\u00a0precision\u00a0cancer therapy, with a focus on externally signal-responsive, bacteria self- responsive, and tumor microenvironment-responsive bacterial systems.<\/p>\n
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