DNAX accessory molecule 1 (CD226) (DNAM-1)

DNAX accessory molecule 1 (DNAM-1), also known as CD226, is a 65 kDa transmembrane glycoprotein and a member of the immunoglobulin superfamily primarily expressed on natural killer (NK) cells, CD8+ T cells, and regulatory T cells (UniProt Q15762). It serves as a potent activating receptor that mediates cellular adhesion and triggers cytotoxic effector functions upon binding to its ligands, CD155 (PVR) and CD112 (Nectin-2), which are frequently overexpressed on the surface of tumor cells and virus-infected cells (PubMed: 29109431). The DNAM-1–ligand complex is a central component of the TIGIT-DNAM-1 axis, a critical immune checkpoint system where DNAM-1 competes for ligand binding with inhibitory receptors such as TIGIT and CD96, which possess higher affinity for the same ligands (Nature Reviews Cancer, PMID: 30224648). In many cancers, the balance of this axis is shifted toward inhibition due to the downregulation of DNAM-1 or the upregulation of TIGIT, leading to immune evasion and T cell exhaustion (PubMed: 31048774). Therapeutic strategies currently focus on restoring DNAM-1 activity, primarily through the use of TIGIT-blocking antibodies that prevent the displacement of DNAM-1 from its ligands, thereby enhancing anti-tumor immunity. Additionally, DNAM-1 is being investigated as a biomarker for response to various immunotherapies, as its presence on tumor-infiltrating lymphocytes is often required for the efficacy of checkpoint blockade (PubMed: 32433919).

Other names

CD226PTA1TLiSA1Platelet and T cell activation antigen 1DNAM1

Restoration of DNAM-1-mediated immune activation by blocking competing inhibitory receptors (TIGIT, CD96, PVRIG) or potentially through direct receptor agonism.