Gut microbiota-innate immune crosstalk in the initiation and progression of CRC: mechanisms and therapeutic potential.

Colorectal cancer (CRC) is a common malignancy of the digestive system, and its initiation and progression are associated with multiple factors, including genetic alterations, environmental exposures, changes in the gut microbiota, and disruption of immune homeostasis. In recent years, evidence from human observational studies, animal models, and in vitro experiments has shown that the gut microbiota can influence Toll-like receptor and NOD-like receptor signaling, NF-κB activation, the NLRP3 inflammasome, and immunometabolic pathways through multiple mechanisms, including microbial structural components, metabolic signals, virulence factors, and outer membrane vesicles. These effects are associated with functional remodeling of innate immune components such as macrophages, dendritic cells, neutrophils, and natural killer (NK) cells. Conversely, the innate immune system can reshape microbial composition, spatial distribution, and metabolic characteristics through antimicrobial effector molecules, maintenance of the mucosal barrier, release of inflammatory mediators, and phagocytic clearance, indicating a bidirectional regulatory relationship between the gut microbiota and innate immunity. Current evidence suggests that microbiota-innate immune interactions are associated, to varying degrees, with CRC-related pathological processes, including alterations in immune surveillance and the myeloid microenvironment, barrier dysfunction, low-grade inflammation, remodeling of the tumor microenvironment, epithelial-mesenchymal transition-related phenotypes, and immune evasion. Notably, colibactin-associated mutational signatures have been directly demonstrated in the genomes of human CRC tumors, representing one of the relatively rare forms of high-strength mechanistic evidence in microbiota-CRC research. Beyond such a limited number of well-supported mechanisms, however, many specific microbiota-immune interactions and their roles at different pathological stages remain based primarily on animal models, in vitro experiments, or integrative inference, while longitudinal causal evidence in humans remains generally limited. This review focuses on the bidirectional interactions between the gut microbiota and innate immunity in CRC, systematically summarizing their molecular mechanisms, associated pathological processes, and advances in microbiota-targeted interventions, with particular emphasis on distinguishing among different types of evidence, experimental contexts, and levels of causal certainty. In doing so, we aim to provide a more cautious theoretical basis for mechanistic research on the microbiota-immune axis and for the development of precision intervention strategies in CRC.