DNAX accessory molecule 1 (CD226) and its ligands Poliovirus receptor (CD155) and Nectin cell adhesion molecule 2 (CD112) (DNAM-1 axis)

DNAM-1 (CD226) is a potent activating receptor expressed on natural killer (NK) cells and cytotoxic T lymphocytes, where it mediates anti-tumor immunity by recognizing the ligands CD155 (Poliovirus receptor) and CD112 (Nectin-2). These ligands are frequently overexpressed on a wide range of malignancies, including melanoma, acute myeloid leukemia, and multiple myeloma, as a result of cellular stress and DNA damage. Upon binding, DNAM-1 associates with the integrin LFA-1 and triggers signaling through Fyn and PKC, leading to the release of cytotoxic granules and pro-inflammatory cytokines like interferon-gamma. However, the DNAM-1 axis is often subverted in the tumor microenvironment by inhibitory receptors such as TIGIT and PVRIG, which compete for the same ligands with higher affinity, thereby suppressing immune responses. Therapeutic strategies targeting this axis primarily focus on blocking these inhibitory checkpoints to restore DNAM-1-mediated activity or directly targeting the ligands on tumor cells with antibodies and ADCs. Emerging approaches also include the development of DNAM-1-engineered CAR-NK cells to enhance tumor recognition and the use of chemotherapeutic agents to upregulate ligand expression.

Other names

CD226DNAM-1PVRCD155Nectin-2CD112TLiSA1PTA1Necl-5PVRL2HVEBPRR2

The primary mechanism involves the restoration of DNAM-1-mediated activating signals by blocking inhibitory receptors (TIGIT, PVRIG) that compete for the same ligands (CD155, CD112). Other mechanisms include direct blockade of CD155 or CD112 on tumor cells to prevent inhibitory signaling and induce antibody-dependent cellular cytotoxicity (ADCC), and the use of DNAM-1-engineered CAR-NK cells to enhance tumor recognition.