RAS mutation status and immune microenvironment define distinct prognostic landscapes and predict chemotherapy benefit in pMMR colorectal cancer.

PURPOSE: The aim of this study was to define the interplay between K/N-RAS mutational status, tumor immune microenvironment (TIME), and chemotherapy response in patients with proficient mismatch repair (pMMR) colorectal cancer (CRC)-a population refractory to immunotherapy but constituting >90% of CRC cases.

METHODS

We retrospectively analyzed 225 patients with pMMR CRC. Multiplex immunohistochemistry was used to quantify stromal and intraepithelial densities of CD4+, CD8+, CD68+, and CD163+ immune cells, along with expression of β-catenin, CMTM6, and programmed death-ligand 1 (PD-L1). Multivariable Cox regression and interaction tests were performed to identify prognostic and predictive biomarkers.

RESULTS

K/N-RAS status stratified pMMR CRC into two distinct subtypes. In RAS wild-type tumors, high stromal CD4+ T-cell infiltration was independently associated with better prognosis. In RAS-mutant tumors, loss of intraepithelial CD8+ T cells and high CD163+ macrophage density predicted poor survival. Critically, chemotherapy significantly improved overall survival only in specific subgroups, including RAS-mutant, β-catenin-low, CMTM6-low, and CD163-high patients. Formal interaction testing confirmed CD163+ macrophage infiltration as a predictive biomarker for chemotherapy benefit and significant chemotherapy benefit in the CD163-high subgroup (HR = 0.20, p < 0.001).

CONCLUSIONS

RAS mutational status shapes a divergent immune landscape that dictates both prognosis and chemotherapy response in pMMR CRC. Integration of RAS status with key TIME features-particularly CD163-may enable the precise selection of patients most likely to benefit from chemotherapy.