From CMS to iCMS/IMF: Developing Roadmap to Precision Therapy in Colorectal Cancer

Colorectal cancer (CRC) classification has progressed from consensus molecular subtypes (CMS) to epithelial-intrinsic consensus molecular subtypes (iCMS) and the layered intrinsic subtype-MSI-fibrosis (IMF) system that combines intrinsic state, MSI status, and fibrosis. This article reviews biological underpinnings of iCMS/IMF, their relationships to tumor-microenvironment crosstalk, and how single-cell and spatial transcriptomics refine therapeutic stratification by resolving tumor microenvironment heterogeneity and its impact on fibrosis. Prognostic and therapeutic implications are covered, including PD-1 blockade in MSI-high (MSI-H), MAPK-directed therapy in BRAF-mutant disease, and EGFR targeting in selected RAS wild-type (WT) left-sided tumors, and we suggest decision points specifically informed by the activity of the fibrosis axis. A step-by-step procedure is presented for the analysis of bulk and single-cell RNA and formalin-fixed, paraffin-embedded (FFPE) resources, along with open-source tools and reporting standards to make iCMS/IMF calling reproducible in clinics and trials. Future outlooks are outlined with near-term biomarker-drug hypotheses for microsatellite-stable (MSS)-iCMS3 and high fibrosis tumors and key gaps to close for clinical translation. This review outlines a roadmap for precision medicine in colorectal cancer by leveraging the iCMS/IMF framework to integrate pathology and digital pathology, molecular diagnostics, and therapy mapping with FAP-targeted imaging and therapy.