{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T07:02:34Z","timestamp":1779778954967,"version":"3.53.1"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Influenza viruses continue to pose a global health threat, and available antiviral therapies are limited by resistance and reduced efficacy. Host-directed drugs such as MEK inhibitors have emerged as promising alternatives. Zapnometinib, a clinical-stage MEK inhibitor, has shown both antiviral and immunomodulatory activity. However, its impact on antigen presentation at the level of the HLA-I ligandome has not been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Label-free LC\u2013MS\/MS was applied to analyze HLA-I\u2013presented peptides in human lung adenocarcinoma Calu-3 cells. Cells were infected with Influenza A virus (IAV) H3N2\/Fukui and treated with zapnometinib. Surface HLA-I expression was quantified by flow cytometry, and immunopeptidomic analyses were applied to assess ligandome alterations and functional pathway enrichment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Zapnometinib treatment and IAV infection did not significantly alter HLA-I surface expression (fold changes 1.01-1.13, p &amp;gt; 0.05). Immunopeptidomics revealed allotype-specific changes in the relative abundance of HLA-I-presented peptides (approximately 3\u201312% change per allotype), and statistically significant modulation of defined ligand subsets (about 3\u201314% of ligands per condition; log\n                      <jats:sub>2<\/jats:sub>\n                      fold change \u2265 2, adjusted p &amp;lt; 0.05). Functional annotation analysis showed condition-specific enrichment in distinct cellular pathways, such as interferon-induced pathways, including IFI16 upregulation during infection and its downregulation upon MEK inhibition, indicating selective modulation of antiviral responses, cell cycle and RNA-processing pathways under zapnometinib treatment, and adhesion-related pathways under combined treatment. Ligandome remodeling after IAV H3N2\/Fukui infection strongly affected antiviral hubs (IFIH1, DHX58, IFI16), whereas zapnometinib caused no consistent or significant reduction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion\/conclusion<\/jats:title>\n                    <jats:p>This study provides the first evidence that zapnometinib and IAV H3N2\/Fukui induce remarkable effects on the HLA-I ligandome plasticity without substantially affecting overall HLA-I expression. These findings highlight the dual role of MEK inhibitors in modulating both viral replication and immune recognition through pathway- and allotype-specific changes in peptide presentation rather than bulk HLA-I levels. Our results support further investigation of zapnometinib as a host-directed antiviral strategy with the potential to contribute to targeted immunomodulation in antiviral therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1790267","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T06:04:20Z","timestamp":1779775460000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Zapnometinib treatment and influenza A virus infection modulate the HLA class I ligandome in human lung adenocarcinoma cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Hazem","family":"Hamza","sequence":"first","affiliation":[{"name":"Institute of Immunology, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"Virology Laboratory, Environmental Research Division, National Research Centre","place":["Giza, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Georg","family":"Rammensee","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"Cluster of Excellence iFIT (EXC2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"Cluster of Excellence CMFI (EXC2124) \u201cControlling Microbes to Fight Infections\u201d, University of T\u00fcbingen","place":["T\u00fcbingen, 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