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Colorectal cancers (CRC) with KRAS mutations ( KRAS  mut ) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRAS  mut , focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRAS  mut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS ( KRAS  wt ). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRAS  mut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRAS  mut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRAS  mut 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 KRAS  mut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRAS  mut CMS3-classified tissues suggested up-regulated genes, CD40 , CTLA4 , ARG1 , STAT3 , IDO , and CD274 , that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRAS  mut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRAS  mut should consider these transcriptional landscapes.

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