Background: Tumor microenvironment (TME) and tumor-infiltrating immune cells (TIC) greatly participated in the genesis and development of colon cancer (CC). However, there are few researches exploring the dynamic modulation of TME. Methods: In our study, we analyzed the proportion of immune/stromal component and TIC in TME of 473 CC samples and 41 normal samples from The Cancer Genome Atlas (TCGA) database through ESTIMATE and CIBERSORT algorithm. Correlation analysis was carried out to evaluate the association between immune/stromal component in TME and clinicopathological characteristics of CC patients. The difference analysis was performed to obtain the differentially expressed genes (DEGs). These DEGs were further analyzed by gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses, protein–protein interaction (PPI) network construction and COX regression analysis. Transforming growth factor β1 (TGFβ1) was finally overlapping from the above analysis. Furthermore, TGFβ1 was analyzed by paired analysis, Gene Set Enrichment Analysis (GSEA). The intersection between the difference analysis and correlation analysis was also conducted to learn the association between TGFβ1 and TICs.Results: Our result showed that immune component in TME was negatively related with the stages of CC. GO and KEGG enrichment analysis revealed that 1110 DEGs obtained from difference analysis were mainly enriched in immune-related activities. The intersection analysis between PPI network and COX regression analysis indicted that TGFβ1 was significantly associated with the communication of genes in PPI network and the Hazard Ratio (HR) of CC patients’ survival. In addition, TGFβ1 was up-regulated in the tumor samples and significantly related with poor prognosis of CC patients. Further GSEA suggested that genes in TGFβ1 up-regulated group were primarily enriched in immune-related activities and the function of TGFβ1 might depend on the communications with TICs, including T cells CD4 naïve and T cells regulatory (Tregs). Conclusions: The expression of TGFβ1 might be an indicator for tumor immune microenvironment (TIME) of CC and sever as a prognostic factor of CC. Drugs targeting TGFβ1 might be a potential immunotherapy for CC patients in the future.