IGSF8, also referred to as EWI-2, CD316, and PGRL, is a member of the immunoglobulin superfamily (IgSF), which is characterized by extracellular immunoglobulin-like domains. IGSF8 specifically contains four such domains along with a short cytoplasmic tail, enabling its roles in cell-cell adhesion, intracellular signaling, and the organization of cell surface microdomains^1,2. It associates with tetraspanins, such as CD9 and CD81, forming the tetraspanin web, a molecular network that organizes cell-surface proteins into functional microdomains and regulates processes like adhesion, migration, and signaling³. Furthermore, IGSF8 interacts with the ezrin-radixin-moesin (ERM) protein family, linking the tetraspanin web to the actin cytoskeleton and contributing to cell polarity and motility^4,5.

Functionally, IGSF8 acts as an immune checkpoint by suppressing natural killer (NK) cell cytotoxicity through interactions with receptors like KIR3DL2, allowing tumor cells to evade immune detection³. Its expression correlates with poor outcomes in cancer and low antigen presentation, making it a promising target for therapeutic intervention^3,4. Beyond its role in immune modulation, IGSF8 contributes to reproductive biology by participating in sperm-egg fusion².

IGSF8 is expressed across various tissues, including neural and immune cells¹. Disruption of its function enhances cellular migration and inhibits metastasis⁴, highlighting its therapeutic relevance. As a cancer immunotherapy target, IGSF8 has shown potential, particularly when combined with immune checkpoint inhibitors like anti-PD1 antibodies³.

Research into IGSF8 is critical for understanding tumor immune evasion, immunotherapeutic development, and its roles in neural and reproductive biology^1,5.