Soroush Akbari‐Ardabili
The tumour immune microenvironment shapes colorectal cancer progression and therapeutic vulnerability, but host metabolic programmes linked to immune-inflamed tumour states remain incompletely defined. Microbiome-derived and postbiotic-related metabolites influence epithelial, stromal and immune signalling, yet their downstream tumour transcriptomic readouts have rarely been assessed as host-side indicators of immune microenvironment state. Four mechanistically defined postbiotic-related host axes were curated: short-chain fatty acid, tryptophan/AhR, polyamine and ferroptosis/redox. Axis scores were calculated as mean z-standardized expression of curated genes in TCGA colorectal cancers and evaluated in GSE39582. Associations with marker-based immune/stromal signatures, microsatellite instability, cytolytic activity, stage and overall survival were tested using Spearman correlations, Wilcoxon tests and Cox models with false-discovery-rate correction. In TCGA, the tryptophan/AhR axis showed the strongest coupling to marker-based immune and myeloid signatures, including macrophage-, Treg-, NK-cell-, CD8 T-cell-, Th1-like and cytolytic-activity programmes. Tryptophan/AhR, short-chain fatty acid and ferroptosis/redox axes were enriched in MSI-H and immune-high tumours, whereas the polyamine axis showed weaker immune associations. Short-chain fatty acid and ferroptosis/redox axes decreased recurrently in advanced-stage disease across cohorts. No universal prognostic axis emerged, although the short-chain fatty acid axis retained a stage-adjusted association with improved overall survival in GSE39582. Postbiotic-related host transcriptomic axes provide interpretable tumour-level readouts connecting metabolic cues with immune microenvironment states in colorectal cancer. They should be considered hypothesis-generating host-side immune-context readouts rather than ready-to-use clinical signatures.