CD226 (DNAX accessory molecule‑1, abbreviated as DNAM‑1) is a co‑activating receptor mainly expressed on the surface of immune cells. It belongs to the immunoglobulin superfamily and was initially identified as a T‑lineage‑specific activation antigen (TLiSA) and a platelet/T‑cell activation antigen (PTA1); it was subsequently uniformly named CD226. In the immune system, CD226 is constitutively expressed primarily on the surface of cytotoxic T cells (CD8+ T cells), natural killer (NK) cells, and platelets, and plays key regulatory roles in lymphocyte signal transduction, cell‑cell adhesion, cytotoxicity, and cytokine secretion.

(i) Activation process:
CD226 recognizes the ligands CD155 (PVR, poliovirus receptor) and CD112 (Nectin‑2) on the surface of target cells. When CD226 binds to abnormally high levels of CD155 or CD112 on target cells, it initiates a series of intracellular signaling pathways, promoting the cytotoxic activity of NK cells and CTLs, thereby clearing virus‑infected cells or tumor cells.

(ii) Signal transduction:
Upon ligand binding, the intracellular tail of CD226 is phosphorylated by Src family kinases (such as LYN or FYN), which then recruits the adaptor protein GRB2, activating downstream VAV1, PI3K, and PLCγ1, and promoting phosphorylation of ERK and AKT as well as intracellular calcium flux, ultimately enhancing the secretion of effector molecules and cell‑killing function.

(iii) Dynamic balance with inhibitory receptors:
The ligands of CD226, CD155 and CD112, are also ligands for the inhibitory receptors TIGIT and CD96. On resting NK cells, CD226 dominates and promotes activation; after NK cell activation, TIGIT expression is upregulated and negatively regulates cytotoxicity by competitively binding the same ligands. The fine balance between CD226 and TIGIT determines the final effector state of immune cells.

The CD226 pathway is highly active in autoimmune diseases. For example, in ulcerative colitis (UC), the proportion of CD226‑positive T cells is elevated and positively correlates with disease activity. In a type 1 diabetes (T1D) model, blockade of CD226 suppresses the local immune cell imbalance in insulitis. Furthermore, the rs763361 (Gly307Ser) variant of the CD226 gene is a genetic risk factor for multiple sclerosis (MS) and promotes chronic inflammation by enhancing the IFN‑γ signaling pathway in CD8+ T cells.

Anti‑CD226 monoclonal antibodies block the binding of CD226 to its ligands CD112/CD155, thereby inhibiting immune overactivation, and provide a novel therapeutic option for patients with autoimmune diseases, especially those who are non‑responsive or intolerant to existing standard therapies.

(i) Bispecific antibody:
ZG005 (Zelgen Pharmaceuticals) simultaneously blocks PD‑1 and TIGIT, relieving the competitive inhibition of TIGIT on CD226, allowing enhanced binding of CD155 to CD226 and promoting T cell/NK cell activation and proliferation.

(ii) Anti‑CD226 mAb + anti‑PD‑1/L1:
Simultaneously activating the CD226 pathway and blocking the PD‑1/PD‑L1 pathway may produce synergistic anti‑tumor effects.

(iii) Chemotherapy + immunotherapy:
Chemotherapy induces an increase in CD226‑high CD8+ T cells, enhancing the efficacy of subsequent immune checkpoint inhibitor therapy.