BACKGROUND:　Cutaneous　melanoma　(CM)　is　an　aggressive　form　of　skin　cancer　with　limited　treatment　options　for　advanced　stages.　Prognostic　markers　that　accurately　predict　patients＇　outcomes　and　guide　therapeutic　strategies　are　crucial　for　improving　melanoma　management.　SETD2　(SET　Domain-Containing　Protein　2),　a　histone　methyltransferase　involved　in　chromatin　remodeling　and　gene　regulation,　has　recently　emerged　as　a　tumor　suppressor.　Its　dysfunction　is　involved　in　oncogenesis　in　some　cancers,　but　little　is　known　about　its　functions　in　progression　and　therapeutic　response　of　melanoma.　METHODS:　RNA-seq　and　clinical　data　from　public　database　were　used　to　evaluate　the　survival　analysis,　gene　set　enrichment,　IC50　of　therapeutics　and　immunotherapy　response.　SETD2　knock-out　A375　cell　line　(A375SETD2ko)　was　developed　by　Crispr/cas9　and　CCK-8　analysis　and　nude　mice　used　to　evaluate　the　proliferation　and　invasion　of　melanoma　cells　in　vitro　and　in　vivo,　while　Western　blotting　tested　the　MMR-related　protein.　RESULTS:　SETD2　was　commonly　down-regulated　in　melanoma　samples　which　demonstrated　an　unfavorable　survival.　Cells　without　SETD2　expression　tend　to　have　a　more　progressive　and　invasive　behavior,　with　resistance　to　chemotherapy.　However,　they　are　more　sensitive　to　tyrosine　kinase　inhibitors　(TKIs).　They　also　exhibit　inflamed　features　with　lower　TIDE　(Tumor　Immune　Dysfunction　and　Exclusion)　score　and　higher　tumor　mutation　burden　(TMB),　showing　that　these　patients　may　benefit　from　immunotherapy.　CONCLUSIONS:　This　study　revealed　that　SETD2　dysfunction　in　melanoma　implied　a　poor　prognosis　and　chemotherapy　resistance,　but　highly　sensitive　to　TKIs　and　immunotherapy,　highlighting　the　prognostic　and　therapeutic　value　of　SETD2　in　cutaneous　melanoma.