Distinct KRAS mutation subtypes reprogram the tumor microenvironment and shape survival outcomes in colorectal cancer

While KRAS mutations are pivotal oncogenic drivers in colorectal cancer (CRC), their clinical and biological heterogeneity across KRAS subtypes remains poorly understood. We aimed to investigate the associations of distinct KRAS alleles with clinicopathologic characteristics, prognosis, and tumor microenvironment (TME) features. We conducted a retrospective analysis of 1,268 patients with CRC by integrating targeted next-generation sequencing data with clinical outcomes. TME characteristics across KRAS variants were further analyzed using bulk and single-cell RNA sequencing (scRNA-seq). KRAS mutations were present in 45.7% of patients. A distinct prognostic hierarchy emerged among alleles. In patients with stage I-III CRC, G12C and G12V mutations conferred the poorest disease-free survival (DFS), compared to those with KRAS wildtype (hazard ratios [HRs], 9.3 and 4.6, respectively; p < 0.001). Meanwhile, the G12A variant was associated with the worst progression-free survival (PFS) (HR 9.6; p < 0.001) in the CRC patients with stage IV. KRAS alleles were associated with distinct metastatic patterns, with G12V/G12C mutations showing pronounced hepatic tropism and G12A mutations enriched in bone metastasis. Bulk transcriptomic analysis revealed that tumors harboring these aggressive G12A, G12C, and G12V variants displayed significantly lower immune cell infiltration and suppressed interferon response pathways. ScRNA-seq analysis further suggested that this immunosuppressive phenotype may be linked to stromal remodeling, marked by enrichment of pro-tumorigenic CXCL14 + cancer-associated fibroblasts (CAFs) and depletion of protective IGF1 + CAFs, along with altered intercellular communication networks. Our study deconstructs the monolithic view of KRAS-mutant CRC, suggesting that individual KRAS subtypes represent distinct molecular entities associated with unique clinical and biological phenotypes. This allele-specific landscape provides a strong rationale for refining prognostic models and developing tailored therapeutic strategies that target the specific vulnerabilities of each KRAS subtype. Specific KRAS alleles are associated with a prognostic hierarchy: G12C/G12V correlate with the poorest early-stage DFS, while G12A predicts the worst advanced-stage PFS. KRAS subtypes are linked to distinct metastatic organotropism, linking G12V/G12C to hepatic and G12A to bone metastases. Aggressive KRAS variants are characterized by an immune-excluded TME by enriching pro-tumorigenic CXCL14 + CAFs and depleting protective IGF1+/CD74 + CAFs.