Immune-Metabolic Profiling Reveals Functional Heterogeneity Within Colorectal Cancer Consensus Molecular Subtypes

The Consensus Molecular Subtype (CMS) classification provides a widely used transcriptomic framework for colorectal cancer (CRC) stratification with clear prognostic and therapeutic relevance. However, it does not fully capture the immune-metabolic heterogeneity underlying tumor-microenvironment interactions within each subtype. Here, we integrate a validated immune-metabolic gene signature as a functional layer to refine CMS classification and systematically characterize diversity across CMS1-4 tumors. Using transcriptomic data from 2918 CRC samples across three independent cohorts (GSE1, TCGA, and GSE2), we show that CMSs display robust yet distinct immune-metabolic distributions across datasets. CMS4 tumors exhibit glycolytic, stromal-dependent, and immunosuppressive profiles, whereas CMS2 and CMS3 are enriched in oxidative and metabolically flexible states. Importantly, CMS1 tumors segregate into two major immune-metabolic profiles, revealing marked heterogeneity within this immune-activated subtype. These patterns are preserved in metastatic samples, supporting their stability across disease stages. Overall, integrating immune-metabolic profiling into CMSs reveals previously unrecognized functional heterogeneity and provides a refined framework to interpret tumor-microenvironment states. This approach facilitates the identification of context-specific metabolic vulnerabilities with potential clinical relevance.