<p>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Tumor epithelial cells play a crucial role in shaping the tumor microenvironment (TME) and driving cancer progression. This study utilized a multi-omics approach, integrating data from 21 multi-center CRC cohorts (n = 2,767), including single-cell transcriptomics, bulk transcriptomics, spatial transcriptomics, and proteomics. Bioinformatic analyses were combined with in vitro and in vivo experiments for validation. A distinct epithelial subpopulation, ERO1A-positive epithelial cells (ERO1A + Epi), was identified and found to be significantly enriched in advanced-stage CRC, correlating with poor prognosis. ERO1A + Epi cells promoted proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, while in vivo models confirmed their role in tumor growth and liver metastasis. Spatial and intercellular interaction analyses revealed that ERO1A + Epi cells interact with CTHRC1 + cancer-associated fibroblasts (CTHRC1 + CAFs) and SPP1 + macrophages via MDK-LRP1, MIF-(CD74 + CD44), and APP-CD74 signaling pathways, fostering a pro-tumorigenic TME. Co-culture experiments demonstrated that ERO1A + Epi enhances the expression of CTHRC1 and SPP1. A risk prediction model (ETSRM) based on the ERO1A + Epi_TME_Score demonstrated superior prognostic accuracy over 111 existing CRC models. Integrating ETSRM with TNM staging further enhanced survival prediction. Our findings identify ERO1A + Epi as a significant driver of colorectal cancer progression. The ERO1A + Epi_TME_Score-based ETSRM provides a robust prognostic tool, offering new insights into CRC pathogenesis and highlighting potential therapeutic targets for improved patient outcomes.</p> Graphical abstract <p>Summarizes ERO1A-positive tumor epithelial cells in colorectal cancer progression: a multi-omics perspective.</p> <p></p>