The MAPK Pathway Coordinates an Immunosuppressive Microenvironment in Colorectal Cancer: A Single-Cell Guided Prognostic Model.

Abstract

Background: The immunosuppressive tumor microenvironment in colorectal cancer is a key factor in its progression and treatment resistance, yet the coordinated mechanisms of its cellular composition and signaling networks are not fully understood. This study aims to explore the regulatory foundation of this microenvironment and construct a clinically relevant prognostic model through the integration of single-cell and multi-omics analyses.

Methods: We first analyzed single-cell RNA sequencing data from 9 samples, mapping cellular landscapes and inferring intercellular communication networks. By integrating extensive transcriptomic data from public databases, we conducted weighted gene co-expression analysis to identify core functional modules. Additionally, we employed machine learning methods to integrate multi-omics features and construct a prognostic risk scoring model.

Results: Analysis suggested that macrophages and fibroblasts in the tumor microenvironment play a dominant role in intercellular communication through specific chemokine signaling axes. Co-expression network analysis further identified the MAPK signaling pathway as a core module associated with immunosuppressive microenvironmental phenotype. Based on these findings, we developed and preliminarily verified a prognostic risk score comprising 17 genes.

Conclusion: This score may independently predict predicts patient survival and effectively distinguishes tumor subtypes with distinct immune microenvironmental characteristics: the high-risk group shows an immunosuppressive, stroma-rich "cold tumor" phenotype, suggesting higher predictive sensitivity to certain chemotherapies and targeted drugs.