Published online Nov 15, 2026. doi: 10.4251/wjgo.122507
Revised: June 8, 2026
Accepted: June 25, 2026
Published online: November 15, 2026
Processing time: 179 Days and 14.8 Hours
Colorectal cancer (CRC) is characterized by prominent molecular and tumor microenvironment heterogeneity, and is classified into four subgroups according to the Consensus Molecular Subtypes (CMS) system. The CMS4 subtype presents a mesenchymal phenotype and extensive stromal infiltration, accompanied by a poor patient prognosis. Nevertheless, the microbial mechanisms driving its tumor microecology remain unclear.
To delineate the patterns of microbial succession in the tumor microecology of CMS4, and to explore its association with metabolic disturbances and tumor immune evasion.
A total of 11 Chinese patients with CRC were enrolled, including 4 patients with CMS4, 3 with CMS3, 3 with CMS2 and 1 with CMS1. Integrated multi-omics analyses including transcriptomics, immunomics, and microbiomics were performed on tumor samples. The GhostKOALA tool was used for microbial functional annotation. Host-microbe interaction models were constructed to screen for key regulatory genes.
CMS4 samples displayed a sharp depletion in Alistipes indistinctus, reducing butyrate metabolism and secondary bile acid regulation. This vacancy triggered a two-step invasion in which aerotolerant Streptococcus breached the mucosal barriers and consumed local oxygen, allowing obligate anaerobic Fusobacterium to dominate the niche (fold change = 2.32). The resulting microbial community cooperated with M2 macrophages to remodel the extracellular matrix, creating dense physical barriers that excluded T cells and elevated immune exclusion scores. Host-microbe modeling further identified prostate cancer susceptibility candidate 1 as a key gene that was consistently silenced by tumor-enriched bacteria.
This study suggests that Alistipes indistinctus and Fusobacterium may be involved in mesenchymal transition and immune evasion in CMS4 CRC. The proposed microbial succession model holds potential to serve as a prognostic biomarker and therapeutic target for this high-risk subtype, and further validation is warranted.
Core Tip: Consensus Molecular Subtype 4 colorectal cancer exhibits a unique microbial succession pattern. Depletion of Alistipes indistinctus initiates a cascade of pathogenic events, ultimately making Fusobacterium the dominant microbial taxon. This microbial shift may mediate tumor immune exclusion through extracellular matrix remodelling, indicating considerable potential for these microbial signatures to act as prognostic biomarkers and therapeutic targets for this refractory cancer subtype.