Programmed cell death protein 1 (PD- 1) /programmed cell death ligand 1 (PD- L1) blockade is an important therapeutic strategy for melanoma, despite its low clinical response. It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients. We analyzed clinical dataset GSE96619, which contains clinical information from five melanoma patients before and after anti- PD- 1 therapy (five pairs of data). We identified 704 DEGs using these five pairs of data, and then the number of DEGs was narrowed down to 286 in patients who responded to treatment. Next, we performed KEGG pathway enrichment and constructed a DEG- associated protein- protein interaction network. Smooth muscle actin 2 (ACTA2) and tyrosine kinase growth factor receptor (KDR) were identified as the hub genes, which were significantly downregulated in the tumor tissue of the two patients who re-sponded to treatment. To confirm our analysis, we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xeno-graft model. This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD- 1/PD- L1 blockade therapy.