A genome‑wide screen in E. coli reveals metabolic adaptations that enhance intratumoral fitness and bacterial cancer therapy efficacy
Menée à l'aide de lignées cellulaires, de modèles murins et du criblage du génome de la bactérie Escherichia coli, cette étude identifie des gènes bactériens et des voies métaboliques régissant l'adaptation des bactéries à l'environnement intratumoral (utilisation des nutriments disponibles) puis met en évidence l'intérêt thérapeutique d'une souche d'Escherichia coli génétiquement modifiée qui, administrée par voie systémique, peut coloniser la tumeur, remplacer la flore bactérienne et produire un immunostimulant
Despite decades of investigation, the fundamental molecular and cellular principles that enable bacteria to thrive within the tumor microenvironment have yet to be defined. Here, through a genome‑wide functional screen, we identify the bacterial genes and pathways that govern intratumoral fitness. Targeted deletion of nonglucose phosphotransferase systems to align bacterial metabolic preference with tumor metabolite availability promotes bacterial intratumoral fitness. Integrating multiple metabolic adaptations into a single tumor‑avid Escherichia coli strain (Ec‑TA) results in increased tumor colonization, not only after intratumoral delivery but also after intravenous delivery, leading to increased anti‑tumor efficacy when using Ec‑TA engineered to deliver an encoded immunostimulatory payload. Furthermore, Ec‑TA displaces wild‑type bacteria from pre‑colonized tumors when administered systemically, underscoring its potential for locally delivering therapeutics in the presence of resident tumor microbes. These data demonstrate that adapting bacteria to the unique characteristics of the tumor metabolic microenvironment can drive the development of safer and more effective chassis for next‑generation bacterial cancer therapies.
Nature Cancer , article en libre accès, 2026