biostudies-literatureWu MV FoundationRessler Family FoundationMelanoma Research FoundationMelanoma Research AllianceJonsson Comprehensive Cancer Center, University of California, Los AngelesNCI NIH HHSUniversity of California, Los AngelesNational Institutes of Health2864-2877.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC12693071biostudies-literatureUnknown58(11)Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression oImmunityGenomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors.PMC126930712R01CA176111-111P01CA168585R01CA282198R01 CA282198U54 CA274509R01 CA176111Kashani-Sabet MWu MDamoiseaux RGiubellino ALomeli SHDharanipragada PLiu SJohnson DBYang ZMoriceau GPrieto-Granada CNFan JYang SNosrati MKim KBKelley MCLo RSfalseGenomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors.Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression o2025-01-01T00:00:00Z2025 Nov2026-06-06T01:08:26.922Z2026-05-24T03:11:56.891ZS-EPMC126930714117587410.1016/j.immuni.2025.10.001