Pathogenic Roles of Fusobacterium nucleatum in Colorectal Cancer: From Strain Heterogeneity to Host–Pathogen Interactions

Fusobacterium nucleatum (Fn) has emerged as one of the most extensively studied tumor-associated opportunistic pathogens in colorectal cancer (CRC). The central question in Fn–CRC research has shifted from species-level detection or enrichment toward identifying specific lineages with enhanced persistence and tumor-promoting potential under defined host and ecological contexts. Accumulating evidence suggests substantial heterogeneity within Fn at the subspecies and clade levels. Among these, the F. nucleatum subsp. animalis C2 (Fna C2) lineage has been proposed as a candidate high-risk clade with potentially greater adaptability to the gastrointestinal tract and tumor microenvironment. However, current support for Fna C2 is derived mainly from ecological enrichment, comparative genomics, inferred metabolic features, and limited functional observations, while direct clinical and mechanistic validation at the clade level remains limited. Fn has been implicated in CRC progression through multiple interconnected processes, including adhesion and colonization, host signaling activation, inflammatory amplification, immune suppression, and metabolic adaptation. Notably, these pathogenic outputs are unlikely to be uniformly distributed across all Fn lineages, but instead appear to be shaped by the combined influence of bacterial lineage, host molecular context, microbial community structure, and spatial organization within the tumor microenvironment. In this review, we summarize the lineage heterogeneity of Fn, its association with CRC, and the underlying host–pathogen interaction mechanisms. We further discuss implications for high-resolution stratification, risk classification, and clinical translation, emphasizing the need to move from species-level associations toward lineage-resolved and context-aware frameworks.