Engineering bifidobacteria to deliver CRISPR antimicrobials targeting oncogenic Fusobacterium nucleatum in colorectal tumors.

Fusobacterium nucleatum (Fn) is increasingly recognized as a clinically meaningful driver in colorectal cancer (CRC), with recent multi-cohort sequencing studies detecting Fn in 35-45% of tumors and levels approaching 50% in stage II-III cases. Meta-analyses including more than 4000 patients consistently link Fn positivity to higher recurrence risk, shorter overall survival, and reduced response to fluoropyrimidine-based chemotherapy. The Fna C2 lineage shows the strongest association with malignancy, appearing in 29.2% of CRC samples compared with 4.8% of healthy controls (P < 5.6 × 10-15). Engineered Bifidobacterium strains, which naturally accumulate in tumor hypoxic zones at densities near 107 CFU/g, provide a platform for delivering CRISPR antimicrobials capable of reducing targeted microbes by 95-99% in vivo. These findings support efforts to eliminate oncogenic Fn within CRC tumors using precision microbial therapeutics.