Esophageal cancer (ESCA) has the sixth highest mortality rate worldwide and its incidence is increasing every year. Alterations in genes and poor dietary habits may induce ESCA. In addition, the tumor immune microenvironment is one of the most common factors involved in the tumorigenesis and development of ESCA, which may be mediated by tumor-associated macrophages, but the molecular mechanism underlying this is unclear. Therefore, in this study, CIBERSORT was used to understand the distribution of innate-immune cells in ESCA and normal tissues using TCGA database. Weighted gene co-expression network (WGCNA) analysis was used to analyze hub genes linked to M1, M2, and M0, which were the top three enriched cells in ESCA. Gene Set Enrichment Analysis (GSEA) displayed that three signal pathways linked to inflammation were enriched in ESCA: NF-κB regulatory pathway genes for TNF response, IFNα signaling pathway genes, and the energy metabolism-related oxidative phosphorylation pathway. Then, multiple hub genes were identified that had several forms of genetic alterations in ESCA, and many patients exhibited more than two of these alterations simultaneously. The risk assessment showed that three hub genes, CMA1, FGF5, and VEGFD, were identified as independent risk factors for ESCA (p<0.05). The overall 5- and 10-year survival rates were lower in patients with altered FGF5 and VEGFD