Abstract 959: Engineering tumor-avid bacteria as anticancer immunotherapy

Abstract The observation that bacteria colonize tumors, but not normal organs, after intravenous administration has spurred new interest in bacteria as tumor-targeted delivery systems. Since bacteria replicate within the tumor site, intravenous administration of bacteria leads to specific expression of peptide-based therapeutics at the tumor site. However, most prior bacterial cancer therapies have relied on this natural tumor tropism since the mechanisms behind this tumor-specificity are poorly understood. Additionally, clinical trials with bacterial therapeutics have shown lower tumor colonization rates in humans, which limits their translatability. This study used a pooled barcode library approach to screen the E. coli genome for pathways which may influence tumor colonization. We found specific pathways, include glucose catabolism, which promote E. coli tumor colonization, and non-glucose catabolic pathways which inhibit E. coli tumor colonization. KO of these inhibitory metabolic pathways increase E. coli glucose uptake and utilization. This was associated with increased tumor colonization as validated by competitive infection experiments, which was further enhanced when glucose was introduced into the tumor microenvironment. Together, these results support a major role for E. coli glucose catabolism in defining bacterial tumor tropism and suggest a promising method by which bacterial tumor tropism can be fine-tuned. Citation Format: Noah Chen, Mathieu Rouanne, Zaofeng Yang, Tal Danino, Nicholas Arpaia. Engineering tumor-avid bacteria as anticancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 959.