CD58, also known as Lymphocyte Function-Associated Antigen 3 (LFA-3), is a glycoprotein that plays a critical role in immune cell interactions. It is widely expressed on various human tissue cells and acts as a counter-receptor for CD2, which is primarily found on the surface of T and NK cells. The interaction between CD2 and CD58 is an essential component of the immune synapse, facilitating not only cell adhesion but also inducing activation and proliferation of T/NK cells. This interaction triggers a series of intracellular signaling pathways in both the T/NK cells and target cells, which is crucial for immune responses. In addition to its membrane-bound form, a soluble form of CD58 (sCD58) exists in cell supernatants and tissues. sCD58 is considered an immunosuppressive factor that affects T/NK cell-mediated immune responses by influencing the CD2-CD58 interaction. Altered accumulation of sCD58 may contribute to immune suppression of T/NK cells in the tumor microenvironment, making sCD58 a potential target for immunotherapy.