Cd226, also known as DNAM-1 (DNAX-accessory molecule-1), is a co-stimulatory molecule on the surface of immune cells, including T cells, natural killer (NK) cells, and macrophages. It plays a crucial role in the immune response by competing with inhibitory receptors like TIGIT and CD96 for ligands such as CD155 on tumor cells, thereby mediating the activation and effector functions of immune cells. It is involved in multiple pathways related to anti-tumor immunity, immune cell metabolism, and inflammatory regulation [1,2,3,6].

Conditional deletion of CD226 within Foxp3+ cells (Tregs) exacerbates symptoms in murine graft-versus-host disease models. Treg-specific deletion of CD226 increases the Treg cell percentage but weakens their immunosuppressive function with a T helper 1-like phenotype conversion under inflammation. CD226-deficient Treg cells show reduced oxidative phosphorylation and increased glycolysis rates, regulated by the AMPK/mTOR/Myc pathway [4]. In type 1 diabetes, CD226+CCR7-CD8+ cytotoxic T cells show dynamic changes during the peri-remission phase, and CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity in mouse diabetes models [5]. In the context of anti-tumor immunity, CD226loCD8+ T cells at the tumor site have an exhausted phenotype, while CD226hiCD8+ T cells have greater self-renewal and responsiveness. Anti-TIGIT treatment selectively affects CD226hiCD8+ T cells [7].

In conclusion, Cd226 is essential for maintaining the stability and function of immune cells, especially in the context of Tregs, anti-tumor immunity, and in diseases like type 1 diabetes. Gene knockout or conditional knockout mouse models have significantly contributed to understanding its role in these biological processes and disease conditions, providing potential therapeutic targets for related diseases.