Starting from the importance of PD-L1 expressed by tumor cells in dampening the antitumor immune responses [40, 41], with a negative impact on outcomes in melanoma patients [42], and by reason of the literature results demonstrating that the PD-L1+ EVs in the plasma of patients with MM could be a biomarker of ICI resistance [24], we decided to investigate PD-L1+ EVs and its cognate PD1+ EVs isolated from the plasma of patients with MM before initiating ICI therapy. The gene discussed is CD274; the disease is melanoma.