2025 Theses Doctoral

A genome wide screen in Escherichia coli reveals metabolic adaptations that enhance intratumoral fitness and bacterial cancer therapy efficacy

Chen, Noah Lejiang

Despite decades of investigation, the fundamental molecular and cellular principles that enable bacteria to thrive within the tumor microenvironment have yet to be defined. After summarizing the state of bacterial cancer therapy research, we systemically uncover these principles through a genome-wide functional screen that identifies the bacterial genes and pathways which govern intratumoral fitness.

Targeted deletion of non-glucose phosphotransferase systems increases bacterial intratumoral fitness by enhancing glucose utilization, demonstrating that aligning bacterial metabolic preference with tumor metabolite availability promotes colonization and persistence within tumors. Integrating multiple metabolic adaptations into a single tumor avid E. 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 pre-existing bacterial populations when administered systemically, underscoring its distinct utility for locally delivering therapeutics in the presence of resident tumor microbiota. 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.