Preclinical models of renal cell carcinoma and lung squamous cell carcinoma reveal that tumor expression of PD-L2, through the inhibition of the activity of CD8+ T-cells, has a protumor role in the TME and could be involved in the resistance to anti–PCD-1 antibodies, which could be overcome by the combined use of anti–PCD-1 or anti–PD-L2 immune checkpoint blockade. This evidence concerns the gene PDCD1LG2 and renal cell carcinoma.