Metabolic engineering of Salmonella enterica for coupled kynurenine sensing and depletion enhances antitumor efficacy
Immunosuppressive tumor metabolic microenvironment remains a major barrier to effective cancer therapy. Tumor-targeting Salmonella enterica strains were engineered to deplete the intratumoral immunosuppressive kynurenine, triggering metabolic rewiring and fostering an active antitumor immune microenvironment. Equipping S. enterica VNP20009 with bacterial kynureninase enzyme (KynU) and a…
Metabolic engineering of Salmonella enterica has shown promise in treating tumors by targeting the immunosuppressive tumor microenvironment. Scientists have engineered strains of S. enterica to degrade kynurenine, a molecule that promotes tumor growth and suppresses the immune system. By equipping S. enterica VNP20009 with the kynureninase enzyme (KynU) and a kynurenine transporter, researchers were able to efficiently break down kynurenine within the tumor site, leading to a shift in the tumor's metabolic state and an active immune response against the cancer.
The researchers then developed a next-generation strain called AD51, which featured a quorum-sensing controlled system for KynU expression, alongside a kynurenine-dependent growth mechanism and tumor targeting capabilities. When AD51 was injected intratumorally, it triggered strong immune activation and demonstrated superior anti-tumor efficacy in murine ovarian cancer and melanoma models.
Remarkably, AD51 reduced tumor burden by 75% and 84%, respectively, compared to untreated control groups. Furthermore, adding intratumoral exogenous IFN{gamma} to AD51 enhanced immune activation and antitumor efficacy even more, with tumor reduction rates of 75% and 84% in the ovarian cancer and melanoma models, respectively.
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