Macrophages are among the most abundant cells of the tumor microenvironment in head and neck squamous cancer (HNSC). Although the marker gene sets of macrophages have been found, the mechanism by which they affect macrophages and whether they further predict the clinical outcome is unclear. In this study, a univariate COX analysis and a random forest algorithm were used to construct a prognostic model. Differential expression of the key gene, methylation status, function, and signaling pathways were further analyzed. We cross-analyzed multiple databases to detect the relationship between the most critical gene and the infiltration of multiple immune cells, as well as its impact on the prognosis of pan-cancer. FANCE is recognized as hub gene by different algorithms. It was overexpressed in HNSC, and high expression was predictive of better prognosis. It might promote apoptosis through the Wnt/β-catenin pathway. The expression of FANCE is inversely proportional to the infiltration of CD4 + T cells and their subsets, tumor-associated macrophages (TAMs), M2 macrophages, but positively co-expressed with M1 macrophages. In summary, FANCE was identified as the hub gene from the macrophage marker gene set, and it may improve the prognosis of HNSC patients by inhibiting lymphocytes and tumor-associated macrophages infiltration.