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0 reviewsGiant congenital melanocytic nevus (GCMN) is a RAS/RAF mutation-driven syndrome characterized by extensive melanocyticlesions, posing psychological challenges and a lifelong risk of malignancy. Existing treatments like surgical resection and lasertherapy fail to fully remove lesions, and MAPK inhibitors show limited efficacy. This study identified a predominant population ofsenescent cells and a minority of proliferative cells in GCMN, necessitating dual-targeted strategies. We found that the antiapoptotic protein BCL2 is expressed in both senescent and proliferative cells from GCMN patients with various gene mutations.Coexpression of P16 and BCL2 indicated a phenotype of growth arrest and cell survival. BCL2 inhibitors (BCL2i) showed significantcytotoxicity to GCMN cells in vitro. Hypopigmentation and GCMN cell clearance were observed in patient-derived xenograft modelsand in NrasQ61K-mutated and BrafV600E-mutated transgenic models following BCL2i treatment. Histology of regressed GCMNindicated extensive immune cell infiltration, suggesting immune involvement. Single-cell sequencing and immunostaining revealed1234567890();,:that activated neutrophils formed extracellular traps, synergizing with BCL2i to treat GCMN. Neutrophil depletion andimmunosuppression reduce treatment efficacy, highlighting the crucial role of the immune response post-BCL2i treatment. Longterm follow-up showed no recurrence, with neutrophils and T cells residing in the dermis, indicating memory immune reactions.These findings present a promising therapeutic strategy and underscore the translational potential of BCL2i in treating GCMN.Signal Transduction and Targeted Therapy (2025) 10:161 ;