Abstract: EHF ETS (E26 transformation-specific) homologous factor/epithelium-specific ETS factor family member 3, ESE3 is a member of the ETS superfamily. EHF is mainly located in cell nuclei. It is a transcription factor that can directly bind to the promoter region of genes or form a transcription complex with other molecules to enhance or inhibit the transcription of downstream target genes. EHF is involved in multiple cell processes including cell proliferation, differentiation, apoptosis, and senescence. EHF plays a role as a tumor suppressor in cancers such as prostate, pancreatic, esophageal, and colon cancers. However, it acts as an oncogene in oral squamous cell carcinoma, gastric cancer, ovarian cancer, thyroid cancer, head and neck squamous cell carcinoma, and breast cancer. In the immune microenvironment, EHF can regulate the expression of some important immune factors and further affect the infiltration and function of the regulatory T cells, myeloid derived suppressor cells, and dendritic cells. In recent years, the pathophysiological function of EHF in tumors and their immune microenvironment has attracted increasing attention. This article reviews the research progress concerning the structure, function, and mechanism of EHF for the identification of new targets and molecular predictive markers for tumor therapy.