Integrative analysis reveals intra-tumoral microbial enterotypes shape host transcriptomes in colorectal cancer.

The intratumor microbiome and host gene regulation are key contributors to colorectal cancer (CRC), yet their interactions remain unclear. To investigate the interplay between intra-tumoral microbe and host gene, we analyzed paired tumor and normal tissues from 31 patients. Integrated multi-omics analysis identified 4,197 significant bacteria-gene correlation pairs involving 30 bacterial taxa. Patient stratification based on these associations reveals two distinct molecular subgroups characterized by unique microbial signatures and immune profiles. In a mouse model, Bacteroides fragilis alters the tumor immune microenvironment, promoting myeloid-derived suppressor cell (MDSC)-mediated CXCL signaling that impaired CD8+ T cell activation and promotes exhaustion. B. fragilis directly promotes CXCL2 expression and ROS production in MDSCs, which subsequently drives CD8+ T cell exhaustion and immune evasion. These findings reveal that intra-tumoral microbiota influence host transcriptomes and immune modulation in CRC, supporting microbiome-based molecular stratification and offering insights into potential microbiota-targeted therapies.