Background
T cells and natural killer (NK) cells are essential components of the immune system and are regulated by coinhibitory and costimulatory molecules in which the B7 family and CD28 family play significant roles. Previous immune checkpoint studies on B7/CD28 family members, such as PD-1, have led to remarkable success in cancer immunotherapy. However, there is still a need to find new immune checkpoint molecules. Recent studies have demonstrated that HHLA2 exerts inhibitory and stimulatory functions on the immune system by binding to different receptors on different sites. However, the pathways between HHLA2 and its two receptors on T cells and NK cells remain controversial.