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

Area of Science:

• Oncology
• Molecular Biology
• Bioinformatics

Background:

• Colorectal cancer (CRC) classification evolved from Consensus Molecular Subtypes (CMS) to epithelial-intrinsic subtypes (iCMS) and the layered Intrinsic Subtype-MSI-Fibrosis (IMF) system.
• The IMF system integrates intrinsic molecular states, microsatellite instability (MSI) status, and tumor fibrosis for a comprehensive classification.

Purpose of the Study:

• To review the biological basis of iCMS/IMF, their connection to tumor microenvironment (TME) crosstalk, and the role of advanced transcriptomics.
• To explore how single-cell and spatial transcriptomics enhance therapeutic stratification by analyzing TME heterogeneity and fibrosis.
• To outline prognostic and therapeutic implications, including immunotherapy, targeted therapies, and decision points based on the fibrosis axis.

Main Methods:

• Review of existing literature on iCMS/IMF, TME crosstalk, and transcriptomic technologies.
• Analysis of how single-cell and spatial transcriptomics resolve TME heterogeneity and its impact on fibrosis.
• Integration of pathology, molecular diagnostics, and therapy mapping for precision medicine.

Main Results:

• The IMF system provides a refined framework for understanding CRC biology and TME interactions.
• Single-cell and spatial transcriptomics offer deeper insights into TME heterogeneity and its influence on fibrosis.
• Specific therapeutic strategies are suggested for MSI-high, BRAF-mutant, and RAS wild-type tumors, informed by the IMF system.

Conclusions:

• The iCMS/IMF framework facilitates reproducible classification and enhances precision medicine in colorectal cancer.
• Integrating pathology, molecular diagnostics, and therapy mapping with advanced imaging and therapeutics offers a roadmap for future CRC treatment.
• Future research should focus on biomarker-drug hypotheses for microsatellite-stable iCMS3 and high-fibrosis tumors to advance clinical translation.