CD226 (also known as DNAM-1) is a member of the immunoglobulin superfamily and is expressed on the surface of T cells, natural killer (NK) cells, monocytes, and macrophages. It enhances the activation, proliferation, and cytotoxic functions of T cells and NK cells by binding to its ligands CD155 and CD112 and activating downstream signaling pathways such as PI3K-AKT and VAV-1-ERK. CD226 plays a crucial role in anti-tumor immunity, with its high expression associated with better responses to immune checkpoint blockade therapies. However, its function can be inhibited by TIGIT, which competes with CD226 for binding to CD155, thereby dampening immune activation. CD226 is also involved in regulating the function of regulatory T cells (Tregs), and its absence in Tregs can exacerbate inflammatory diseases. Thus, CD226 holds potential not only in cancer immunotherapy but also in the study of autoimmune diseases.