Our findings are as follows: (i) HDAC2 upregulates ISG expression by deacetylating H4K16, increasing the recruitment of RNA polymerase II to the promoter; and (ii) NOS1 reduces STAT1-mediated recruitment of HDAC2 to the ISG promoter and deacetylation of H4K16 by S-nitrosylation of HDAC2-C262/C274, which results in inhibition of IFN signaling and tumor lymphocyte infiltration, thereby promoting lung metastasis of melanoma. This evidence concerns the gene NOS1 and melanoma.