{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:15:50Z","timestamp":1785413750725,"version":"3.56.0"},"reference-count":65,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"German Cancer Aid","doi-asserted-by":"publisher","award":["70114488"],"award-info":[{"award-number":["70114488"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"award":["70114488"],"award-info":[{"award-number":["70114488"]}],"id":[{"id":"https:\/\/ror.org\/01wxdd722","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["514808265"],"award-info":[{"award-number":["514808265"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"award":["514808265"],"award-info":[{"award-number":["514808265"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Head and neck squamous cell carcinomas (HNSCCs) are highly immunosuppressive, and tumor-associated macrophages constitute a major component of HNSCC tumor microenvironments. Here, we investigate the effects of circulating small extracellular vesicles (sEVs) from HNSCC patients on primary macrophages, to elucidate systemic sEV-mediated immune regulation in HNSCC patients. Methods: sEVs were isolated from plasma by size-exclusion chromatography. Internalization of PKH26-labeled sEVs was demonstrated, and mass spectrometry analysis was performed on HNSCC sEVs and sEV-treated macrophages. NF-\u03baB activation was investigated by Western blot and p65 translocation assay. Downstream, mRNA and protein levels of cytokines and chemotaxis of T cells were investigated. Results: Proteomic analysis revealed time-dependent modulation of the macrophage proteome and NF-\u03baB signaling pathway, which was confirmed by Western blot and p65 translocation assay. sEVs from HNSCC patients negative for human papillomavirus type 16 (HPV) differentially modulated NF-\u03baB signaling and sEV uptake mechanisms compared with sEVs from HPV-positive patients and healthy donors. Conclusions: Circulating sEVs derived from HNSCC patient plasma modulate macrophage proteomic profiles and NF-\u03baB signaling. HPV16 status was associated with differential sEV-mediated macrophage regulation, suggesting a potential role of sEVs in systemic immune modulation in HNSCC.<\/jats:p>","DOI":"10.3390\/cancers18142219","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T16:16:44Z","timestamp":1783613804000},"page":"2219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma-Derived sEVs from HNSCC Patients Differentially Regulate NF-\u03baB Signaling in Macrophages Depending on the HPV Status"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7931-4831","authenticated-orcid":false,"given":"Diana","family":"Huber","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Technical University Munich, 81675 Munich, Germany"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian von","family":"Strachwitz","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0683-7659","authenticated-orcid":false,"given":"Linda","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Pietrowska","sequence":"additional","affiliation":[{"name":"Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland"},{"name":"Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Gawin","sequence":"additional","affiliation":[{"name":"Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland"},{"name":"Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dapi Meng-Lin","family":"Chiang","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Guder","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Technical University Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Lotfi","sequence":"additional","affiliation":[{"name":"Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden Wuerttemberg-Hessia, 89075 Ulm, Germany"},{"name":"Institute for Transfusion Medicine, University Hospital Ulm, 89075 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0405-851X","authenticated-orcid":false,"given":"Shosei","family":"Kishida","sequence":"additional","affiliation":[{"name":"Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3192-1019","authenticated-orcid":false,"given":"Michael W.","family":"Pfaffl","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3062-459X","authenticated-orcid":false,"given":"Barbara","family":"Wollenberg","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Technical University Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas K.","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6456-5508","authenticated-orcid":false,"given":"Cornelia","family":"Brunner","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany"},{"name":"Core Facility Immune Monitoring, Medical Faculty, Ulm University, 89075 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Nicole","family":"Theodoraki","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Technical University Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat. 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