Re-arming checkpoint blockade in MSS colorectal cancer: A precision-microbiome playbook from mechanisms to clinic.

Immune checkpoint blockade transforms outcomes for the 15% of colorectal cancers (CRCs) with mismatch-repair deficiency; yet most tumours remain refractory. Beneficial gut microbes can change this. Akkermansia muciniphila, Bacteroides fragilis, and short-chain fatty acid producers prime dendritic cells to produce interleukin (IL)-12, polarise Th1 cells, and reinvigorate CD8+ T-cells. Antibiotics, Western-style diets, and Fusobacterium nucleatum foster myeloid suppression and β-catenin- or IL-17-mediated signalling, which blunt checkpoint activity. Multi-omics analyses link biosynthetic genes for inosine, riboflavin, and folate to durable clinical benefit. Faecal microbiota transplantation from responders has produced objective regressions in otherwise refractory microsatellite-stable disease. This narrative review maps CRC-microbiota-immune crosstalk, evaluates biomarkers and interventions, and proposes a CRC-specific, three-tiered clinical algorithm. We outline standards for trial design and manufacturing processes to facilitate the translation of microbiota-guided therapy into routine practice.