Abstract: Immune checkpoint inhibitors （ICI） have brought transformative innovation for the treatment of malignancies. Though programmed death 1（PD-1） and programmed death ligand 1（PD-L1） have been the major targets for immune therapy, the interplay of human immune system and tumors is very complex because there are other checkpoint molecules and their interaction with many other proteins with differential affinity to mediate diverse cellular processes and immune response. So, while assessing the efficacy of antibody inhibitors against PD-1 or PD-L1, the action on other ligands or binding proteins by blocking PD-1 or PD-L1 and related effects should be included instead of simply taking it as to activate immune system by single checkpoint blockade. PD-L2 acts as a secondary ligand for PD-1 with debated role of complicated immune modification. Early studies just took PD-L2 as a ligand for PD-1. However, recently more and more data showed that PD-L2 could have substantial role in the prognosis and prediction of clinical immune treatment in cancer patients. In this paper, the role of PD-L2 in tumor immunotherapy is briefly described.