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In this study, we define the oncogenic role of METTL3 in melanoma development and progression. Building on this insight, we examine our recently designed peptide inhibitor <jats:bold>RM3<\/jats:bold>, which targets the binding interface of METTL3\/14 complex for disruption and subsequent ubiquitin\u2010mediated proteasomal degradation via the E3 ligase STUB1. <jats:bold>RM3<\/jats:bold> treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno\u2010related genes following <jats:bold>RM3<\/jats:bold>\u2010mediated suppression of METTL3\/14 N<jats:sup>6<\/jats:sup>\u2010methyladenosine (m<jats:sup>6<\/jats:sup>A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of <jats:bold>RM3<\/jats:bold> with anti\u2010PD\u20101 antibody results in significantly higher beneficial tumor response in vivo, with a good safety profile. Collectively, these findings not only delineate the oncogenic role of METTL3 in melanoma but also showcase <jats:bold>RM3<\/jats:bold>, acting as a peptide degrader, as a novel and promising strategy for melanoma treatment.<\/jats:p>","DOI":"10.1002\/anie.202407381","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T11:35:15Z","timestamp":1723548915000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Peptide Degrader\u2010Based Targeting of METTL3\/14 Improves Immunotherapy Response in Cutaneous Melanoma"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7378-2718","authenticated-orcid":false,"given":"Hong","family":"Han","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Hunan University, School of Biomedical Sciences Hunan University  Changsha P. R. 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