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Here, we present Epitope Generation Gateway (EGG), a containerized pipeline that streamlines discovery and prioritization across variant types and human leukocyte antigen (HLA) contexts. EGG coordinates established components, Mutect2 for somatic single nucleotide variations (SNVs) and indels, STAR-Fusion for fusion events, ArcasHLA for HLA typing, and pVACtools for epitope sequence prediction, then augments peptide-level scores with biological context. For each patient, EGG builds co-expression and protein\u2013protein interaction networks, uses centrality measures and CRISPR dependency data (DepMap) to flag genes important for tumor fitness, and annotates source genes with gene ontology terms, Hallmarks of Cancer processes, and IntOGen driver status. Results: This multi-layer information supports ranking of candidates that are predicted to be presented and that arise from genes essential to tumor fitness or embedded in key pathways, providing a framework to nominate epitopes whose source genes may be less dispensable under immune pressure. As a case study, we applied EGG to 30 TCGA skin cutaneous melanoma patients, demonstrating end-to-end execution and producing prioritized epitopes that emphasize peptides and alterations in high-centrality, dependency-supported essential genes. Conclusions: Overall, EGG links epitope prioritization to tumor systems biology and evolutionary rationale, prioritizing biologically contextualized cancer vaccine candidates from SNVs, indels, fusions, and splicing-derived epitopes while streamlining dataset analysis. EGG is available from GitHub at https:\/\/github.com\/fhaive\/epitope_generation_gateway.<\/jats:p>","DOI":"10.1093\/gigascience\/giag095","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:47:49Z","timestamp":1790855269000},"source":"Crossref","is-referenced-by-count":0,"title":["Epitope Generation Gateway: A biological context-dependent approach to cancer vaccine development"],"prefix":"10.1093","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2549-2680","authenticated-orcid":false,"given":"Luca","family":"Mannino","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, Arvo Ylp\u00f6n katu 34, Kauppi, 33520 , Tampere ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3997-2339","authenticated-orcid":false,"given":"Michele","family":"Fratello","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, Arvo Ylp\u00f6n katu 34, Kauppi, 33520 , Tampere ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6577-2691","authenticated-orcid":false,"given":"Jacopo","family":"Chiaro","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Faculty of Pharmacy ImmunoViroTherapy Lab, Drug Research Program, University of Helsinki, Viikinkaari 5 E, Viikki, 00790 , Helsinki ,","place":["Finland"]},{"name":"Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Viikinkaari 5 D, Viikki, 00790 , Helsinki ,","place":["Finland"]},{"name":"Translational Immunology Program (TRIMM), Faculty of Medicine Helsinki University, University of Helsinki, Haartmaninkatu 8, Meilahti, 00290 , Helsinki ,","place":["Finland"]},{"name":"Digital Precision Cancer Medicine Flagship (iCAN), University of Helsinki. 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Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 , Kuopio ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3374-1492","authenticated-orcid":false,"given":"Angela","family":"Serra","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, Arvo Ylp\u00f6n katu 34, Kauppi, 33520 , Tampere ,","place":["Finland"]},{"name":"Tampere Institute for Advanced Study, Tampere University, Kalevantie 4, City Centre Campus, 33100 , Tampere ,","place":["Finland"]},{"name":"Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, Viikki, 00790 , Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7593-2708","authenticated-orcid":false,"given":"Seppo","family":"Yl\u00e4-Herttuala","sequence":"additional","affiliation":[{"name":"A.I. 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Haartmaninkatu 8, Meilahti, 00290 , Helsinki ,","place":["Finland"]},{"name":"Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, Via Sergio Pansini 5, Zona Ospedaliera, 80131 , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2554-9879","authenticated-orcid":false,"given":"Antonio","family":"Federico","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, Arvo Ylp\u00f6n katu 34, Kauppi, 33520 , Tampere ,","place":["Finland"]},{"name":"Tampere Institute for Advanced Study, Tampere University, Kalevantie 4, City Centre Campus, 33100 , Tampere ,","place":["Finland"]},{"name":"Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, Viikki, 00790 , Helsinki 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