Peptide degrader‐based targeting of METTL3/14 improves immunotherapy response in cutaneous melanoma

Abstract METTL3 has emerged as a promising therapeutic target in cancer treatment, although its oncogenic functions in melanoma development and potential for therapeutic targeting drug have not been fully explored. 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 RM3 , which targets the binding interface of METTL3/14 complex for disruption and subsequent ubiquitin‐mediated proteasomal degradation via the E3 ligase STUB1. RM3 treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno‐related genes following RM3 ‐mediated suppression of METTL3/14 N 6 ‐methyladenosine (m 6 A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of RM3 with anti‐PD‐1 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 RM3 , acting as a peptide degrader, as a novel and promising strategy for melanoma treatment.