Microbiota-Driven Bacterial Therapies for Colorectal Cancer: Mechanistic Insights, Delivery Engineering, and Clinical Translation

The gut microbiota plays a critical role in colorectal cancer (CRC) initiation, progression, metastasis, and therapeutic response through complex interactions among microbial communities, metabolites, and the tumor immune microenvironment. Increasing evidence reveals that CRC-associated bacteria regulate tumor development by inducing genomic instability, inflammatory remodeling, immune escape, and metabolic reprogramming, while microbiota-derived metabolites serve as both pathogenic mediators and therapeutic targets. In parallel, advances in synthetic biology and materials engineering have enabled the development of bacteria-based therapeutic platforms with improved targeting, controllability, and translational potential. This review summarizes recent progress in microbiota-driven bacterial therapies for CRC, focusing on the mechanistic links between tumor-associated microbes, microbial metabolites, and immune regulation. We discuss emerging therapeutic strategies, including microbiome restoration approaches, fecal microbiota transplantation, tumor-targeting oncolytic bacteria, engineered bacterial delivery systems, bacteria-derived outer membrane vesicles, bacteriophage-based platforms, and bacteria–material hybrid systems. Particular emphasis is placed on how material engineering strategies, including hydrogel encapsulation, responsive carriers, microneedle systems, and biohybrid interfaces, overcome key barriers associated with bacterial viability, localization, activation control, and biosafety.This review offers valuable insights and technical guidance for the clinical application and future development of bacteria-based therapies in CRC treatment. © 2026 Wiley-VCH GmbH.