Ephrin type-A receptor 2–T-cell surface glycoprotein CD3 epsilon chain interface (EphA2–CD3ε interface)

The EphA2–CD3ε cell–cell interface is a recently identified non-canonical interaction between the receptor tyrosine kinase EphA2, which is frequently overexpressed in various solid tumors, and the CD3ε subunit of the T-cell receptor (TCR) complex. Unlike traditional TCR recognition that requires MHC-peptide complexes, EphA2 acts as a direct functional ligand for CD3ε, enabling T cells to recognize and respond to tumor cells in an MHC-independent manner. This interaction facilitates the formation of a functional immune synapse, leading to T-cell activation and subsequent tumor cell lysis. This interface is a significant target for cancer immunotherapy, particularly for the development of bispecific T-cell engagers (BiTEs) and CAR-T therapies that exploit this direct binding to recruit and activate T cells against EphA2-positive malignancies. Understanding this interface provides a blueprint for developing next-generation immunotherapies that bypass traditional HLA-restriction and overcome tumor immune evasion.

Other names

EphA2-CD3e complexEphA2-CD3 epsilon interactionEphA2-TCR interfaceEphA2-CD3 cell-cell junction

Direct binding of EphA2 on tumor cells to the CD3ε subunit of the T-cell receptor (TCR) complex on T cells triggers TCR signaling and T-cell mediated cytotoxicity in an MHC-independent manner.