The -Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer.

Colorectal cancers (CRC) with mutations () are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of , focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of in patients with CRC was investigated and overall survival (OS) was compared with wild-type (). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of in the TME regions of CMS3-classified CRC tissues. CRC patients with were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of CMS3-classified tissues suggested up-regulated genes, , , , , , and , that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of in immunosuppressive TME. Future studies and clinical trials in CRC patients with should consider these transcriptional landscapes.