{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:03:02Z","timestamp":1791201782272,"version":"4.2.0"},"reference-count":48,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["247354600"],"award-info":[{"award-number":["247354600"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["247377969"],"award-info":[{"award-number":["247377969"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["426788273"],"award-info":[{"award-number":["426788273"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["516868494"],"award-info":[{"award-number":["516868494"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["518551069"],"award-info":[{"award-number":["518551069"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2026,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Despite substantial clinical benefit from immune checkpoint inhibitors (ICI), advanced melanoma remains challenging due to frequent treatment resistance. Resistance may be intrinsic (primary) or emerge over time (secondary). Biomarkers predicting distinct resistance phenotypes before therapy are lacking. As key mediators of cellular communication, extracellular vesicles (EVs) represent promising biomarkers. This study aimed to identify baseline EV proteome\u2013derived pathways and biomarkers associated with overall, primary, and secondary resistance to ICI in advanced melanoma and to derive biomarker signatures predictive of progression\u2010free survival (PFS). EVs were isolated from pretreatment plasma samples of 46 patients with advanced melanoma using size exclusion chromatography and ultracentrifugation. Proteomic profiling was performed by liquid chromatography\u2013mass spectrometry using DIA\u2010NN. Pathway enrichment and network analyses were conducted using Reactome, Metascape, Cytoscape, and DAVID. Resistance\u2010associated proteins were integrated into composite biomarker signatures and evaluated for association with PFS. Overall resistance was characterized by enrichment of platelet\u2010 and complement\u2010associated pathways. Primary resistance was associated with enhanced Fc gamma receptor (FCGR) signaling and downregulation of KSRP\u2010associated post\u2010transcriptional regulatory processes. In contrast, secondary resistance was preceded by distinct baseline EV proteomic patterns involving complement activation and reduced hemostasis\u2010 and platelet\u2010related pathways. EV\u2010derived biomarker signatures for overall, primary, and secondary resistance independently discriminated patients according to PFS. Baseline plasma EV proteomics reveals distinct systemic biological programs associated with different resistance phenotypes to ICI in advanced melanoma. EV\u2010derived biomarker signatures enable stratification by PFS and warrant validation in larger, multicentric cohorts.<\/jats:p>","DOI":"10.1002\/ijc.70650","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T03:45:30Z","timestamp":1783914330000},"page":"2824-2834","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Plasma Extracellular Vesicles Proteome: Predictors of Resistance in Immunotherapy of Advanced Melanoma"],"prefix":"10.1002","volume":"159","author":[{"given":"Julian","family":"K\u00f6tt","sequence":"first","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3999-5902","authenticated-orcid":false,"given":"Glenn","family":"Geidel","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen M. T.","family":"Roeper","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucija","family":"A\u010dkar","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bente","family":"Siebels","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometry and Proteomics, Center of Diagnostics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Vo\u00df","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometry and Proteomics, Center of Diagnostics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Schl\u00fcter","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometry and Proteomics, Center of Diagnostics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kilian","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometry and Proteomics, Center of Diagnostics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"R\u00fcnger","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8096-7402","authenticated-orcid":false,"given":"Tim","family":"Zell","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Deitert","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Zeinal\u2010Abedini","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Heidrich","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Institute of Tumor Biology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan W.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Pantel","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Institute of Tumor Biology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-9511","authenticated-orcid":false,"given":"Daniel J.","family":"Smit","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Institute of Tumor Biology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoffer","family":"Gebhardt","sequence":"additional","affiliation":[{"name":"Fleur Hiege Center for Skin Cancer Research University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Dermatology and Venereology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2407417"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102022\u2010005921"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/EDBK_240837"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104258"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2016.05.006"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14404"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102019\u2010000398"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425\u2010019\u20100780\u20100"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.017"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010immunol\u2010070621\u2010030155"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010023\u201001909\u20105"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010023\u201001898\u20105"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.1061982"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114721"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1442573"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471143030.cb0322s30"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010018\u20100082\u2010x"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201062237\u20104"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100638\u2010x"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3901"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.TIR120.002155"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201009234\u20106"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1000"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1655"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201014\u20100157"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2122716119"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102020\u2010001719"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17132162"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2024.115159"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2025.115639"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010022\u201000763\u20108"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11182800"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010170278"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1051280"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106376"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.08.004"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110021"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326\u20106066.CIR\u201023\u20100389"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11091482"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/4726532"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2013.0143"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010021\u201000899\u20100"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010025\u201003769\u20101"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201018392\u20101"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885\u2010024\u201012105\u2010z"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.70650","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ijc.70650","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.70650","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:45:31Z","timestamp":1791200731000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.70650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,12]]},"references-count":48,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,12,1]]}},"alternative-id":["10.1002\/ijc.70650"],"URL":"https:\/\/doi.org\/10.1002\/ijc.70650","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,12]]},"assertion":[{"value":"2026-02-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}