Authors
Kontham Kulangara Varsha, Akeem Santos, Tingting Xiao, Zeneng Wang, Rashmi Bharti, Mahima Arora, Austin M Williams, John Peterson, Justin D Lathia, Stanley L Hazen, Nan Zhang, Philip Ahern, Ofer Reizes, Mohammed Dwidar
Published in
bioRxiv : the preprint server for biology. Sep 24, 2026. Epub Sep 24, 2026.
Abstract
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 kynurenine transporter enabled efficient intratumoral kynurenine degradation. We then developed a next-generation strain, AD51, combining quorum-sensing controlled KynU expression with kynurenine-dependent growth and tumor targeting. AD51 induced robust immune activation and exhibited better anti-tumor efficacy. The addition of intratumoral exogenous IFNγ to AD51 synergistically enhanced immune activation and antitumor efficacy in murine ovarian cancer and melanoma models, reducing tumor burden by 75% and 84%, respectively, compared with untreated controls (p<0.0001 for both). Our data establishes a framework for engineering bacteria to target and degrade tumor immunosuppressive metabolites while coupling bacterial growth to metabolite availability, paving the way for more precise and programmable microbial therapies.
PMID:
42818072
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.
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