Abstract Melanoma’s robust immunotherapy responses are driven by a high mutational load and diverse antigen landscapes, yet the mechanisms linking these features to immune outcomes remain incompletely understood due to the absence of a system-level view. To address this gap, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) performed a large-scale, multi-omics melanoma study spanning 164 primary tumors and metastases. We integrated 13 omic layers — including, for the first time at this scale, immunopeptidomics, metabolomics, and ubiquitination and glycosylation post-translational modifications (PTMs) — to construct a holistic view of tumor immunogenicity. Mass-spectrometry-based HLA-I immunopeptidomics identified 315,225 unique HLA-I-bound peptides, including 1,138 tumor antigen candidates. Of these, 33% are tumor-associated antigens and 22% are lineage-specific antigens, consistent with recent findings that most tumor antigens in cancers derive from unmutated genomic sequences. Tumor antigen load correlates significantly with CD8+ T cell infiltration. Notably, antigens from a few MAGEA-family genes correlates with CD8+ T cell percentages, suggesting MAGEA antigens may drive CD8+ T cell recruitment. We provided the most comprehensive tumor-derived metabolomic profiling in melanoma to date, linking metabolic states to tumor biology and the immune context. In a subset of patients with relatively low tumor antigen loads and limited immune infiltration, ether lipid metabolism emerges as a regulator of primary tumor homeostasis, whereas metastases exhibit upregulated mitochondrial metabolism. Unsupervised clustering of protein ubiquitination data identifies a subgroup with markedly worse survival, characterized by high ubiquitination of the IFN signaling pathway and ubiquitination-dependent activation of AKT1. This ubiquitin-IFN cluster is not detectable in global proteomics, highlighting ubiquitination-mediated regulation of inflammatory signaling and tumor progression. Glycoproteomics-based clustering reveals a lysosome-active subgroup, supported by upregulation of lysosome-associated degradative and lipid-metabolizing pathways. We also observe sex-specific differences: in males, lysosome-active glyco-cluster membership associates with significantly worse survival, a pattern not seen in females. Although sex differences in immunotherapy responses have been reported, mechanisms remain unclear; these data offer insights into sex-specific immunotherapy outcomes. Collectively, this multi-layer resource links tumor genetics, transcriptomics, proteomics, PTMs, and metabolomics to antigen presentation and immune signaling. It unravels the molecular logic underlying immune evasion, offering a comprehensive multi-omic atlas to inform patient stratification and design of combination immunotherapies in melanoma. Citation Format: Pei Wang, CPTAC Proteomics Characterization Melanoma Study Working Group. Decoding melanoma immunogenicity: A comprehensive proteogenomic, immunopeptidomic, and metabolomic atlas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1284.
Wang et al. (Fri,) studied this question.