Bioinformatics analysis and experimental validation identified HMGA2/microRNA-200c-3p/LSAMP/Wnt axis as an immunological factor of patients with colorectal cancer. American journal of cancer research Colorectal cancer (CRC) is one of the most common malignant cancers. The tumor microenvironment (TME) plays an important role in tumor progression and affects the prognosis of CRC patients. However, the TME has been poorly characterized and studies aiming to identify the biomarkers or combined risk scores of CRC patients are limited. Here, we overlapped differentially expressed genes and stromal/immune-score-related modules to identify immune- and stromal-related genes in CRC patients. These genes were fed into the LASSO-Cox regression analysis for dimensionality reduction to establish a TME-associated risk model. A high TME-associated risk score was identified as an unfavorable prognostic factor in The Cancer Genome Atlas and Gene Expression Omnibus datasets, as well as in a subgroup analysis, stratified by gender, age, microsatellite instability, and tumor lymph node metastasis stage. Ten genes were mutated more frequently in the high TME-associated risk score group; these mutations may be related to changes in the TME and the response to immunotherapy. Thus, a lower TME-associated risk score may indicate a better response to immunotherapy and longer overall survival. Experimental validation demonstrated that , a novel TME-associated-risk-score-related gene, increased sensitivity of CRC to CD8-T-cell-mediated cytotoxicity. A mechanistic investigation showed that the HMGA2/microRNA-200c-3p/LSAMP/Wnt axis was an immunological factor in CRC patients. To conclusion, we demonstrated that the TME-associated risk score model could be a reliable prognostic biomarker for CRC patients and highlighted the significance of the HMGA2/microRNA-200c-3p/LSAMP/Wnt axis in the oncoimmunology of CRC.