Bioengineered Networking Microbes for Targeted Colon Cancer Therapy

About This Grant

Project Summary Colon cancer remains a critical global health challenge, intensified by the rising incidence of early-onset disease and the persistence of immunologically cold and metastatic tumors that evade conventional therapies. To address these unmet needs, this project develops bioengineered networking microbes, a coordinated system of genetically modified bacteria designed to selectively target tumors and reprogram the host immune environment. We have developed genetically modified Salmonella (GMS) engineered to deliver TRAIL and capable of homing to tumor sites, colonizing the tumor microenvironment, and initiating localized inflammatory responses that increase tumor immunogenicity. In multiple preclinical mouse models, TRAIL-expressing GMS induce potent tumor cell apoptosis, amplify immune activation through the release of tumor-associated antigens, inhibit tumor growth, prolong survival, and reduce metastatic spread. Complementing this oncolytic platform, we also engineer beneficial gut bacteria to restore microbial balance, reduce inflammation, and modulate metabolites implicated in colon cancer progression. By integrating tumor-targeting bacteria with microbiome-restorative strains, we propose a synergistic therapeutic approach in which engineered microbes communicate and cooperate to enhance tumor targeting, strengthen anti-tumor immunity, and improve overall treatment efficacy. Animal models are essential for proposed research to evaluate the safety, biodistribution, and therapeutic efficacy of the engineered microbial consortium within the complex tumor and immune microenvironment. They also enable investigation of host-microbiome-tumor interactions and cooperative microbial behaviors that cannot be adequately replicated in vitro. If successful, this project will establish a transformative paradigm in colon cancer therapy-leveraging networked, multifunctional microbes as both precise local activators of anti-tumor immunity and systemic modulators of gut health to achieve durable and broadly applicable therapeutic responses.