Engineering Salmonella-based Platforms for Immunotherapy Against Immunologically Silent Tumors

Bacterial therapy for cancer is rapidly gaining traction as a powerful approach for treating solid tumors. Among the various bacterial candidates, Salmonella enterica serovar Typhimurium (S. Typhimurium) stands out due to its natural propensity to home in on tumors, its robust innate immunostimulatory properties, and the availability of multiple virulence-attenuating mutations that enhance safety. Nevertheless, key challenges persist-particularly the risk of systemic toxicity and limited efficacy against immunologically “cold” tumors that fail to mount strong immune responses. To overcome these obstacles, we will harness our extensive expertise to transform S. Typhimurium into a next-generation therapeutic platform. The proposed research will address key barriers in bacterial-based cancer therapies by 1) leveraging novel mechanisms of innate immune stimulation that can potentially overcome tumor-specific resistance to innate immune agonists, broadening the applicability of bacterial therapies; 2) integrating safety and efficacy using bacterial minicells that while ensuring a safer delivery, do not compromise their ability to stimulate the immune system; and 3) specifically engineering Salmonella to deliver antigens capable of engaging pre-existing CD8+ T cells, thus enabling targeted immune responses against antigenically diverse tumors. Together, these strategies are poised to open the door to future clinical applications of bacterial-based therapies for solid tumors—particularly those that are otherwise unresponsive to conventional immunotherapy. Project Number: 1R21CA306936-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jorge Galan | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $432,125 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CDPT-C (08)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11263977