Based on the crucial roles of PD-L2 in immune activity and tumour progression, a depth understanding of PD-L2 regulation, including genomic alteration, epigenetic modification, transcriptional regulation, post-transcriptional modification, translational regulation, and post-translational modification (Table 1 and Fig. 2), may provide promising combination strategies for predicting and improving PD-1 blockage efficiency. This evidence concerns the gene PDCD1LG2 and neoplasm.