2. Academic Validation
  3. Constitutive expression of the transcriptional co-activator IκBζ promotes melanoma growth and immunotherapy resistance

Constitutive expression of the transcriptional co-activator IκBζ promotes melanoma growth and immunotherapy resistance

  • Nat Commun. 2025 Jun 25;16(1):5387. doi: 10.1038/s41467-025-60929-5.
Antonia Kolb 1,  Ana-Marija Kulis-Mandic 1,  Matthias Klein 2 3,  Anna Stastny 1,  Maximilian Haist 1 4,  Vanessa Votteler 5 6 7,  Beate Weidenthaler-Barth 1,  Tobias Sinnberg 7 8 9,  Antje Sucker 10,  Gabriele Allies 10,  Lea Jessica Albrecht 10,  Alpaslan Tasdogan 10,  Andrea Tuettenberg 1 3,  Matthias M Gaida 3 11 12,  Carsten Deppermann 3 13,  Henner Stege 1,  Dirk Schadendorf 10,  Stephan Grabbe 1 3,  Klaus Schulze-Osthoff 5 6 7,  Daniela Kramer 14 15
Affiliations

Affiliations

  • 1 Department of Dermatology, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
  • 2 Institute for Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 3 Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
  • 4 Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung) and German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany.
  • 6 Department of Molecular Medicine, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
  • 7 Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Eberhard Karls University Hospital Tübingen, Tübingen, Germany.
  • 8 Department of Dermatology, Eberhard Karls University Hospital Tübingen, Tübingen, Germany.
  • 9 Department of Dermatology, Venereology and Allergology, Charité - University Medical Center Berlin, Berlin, Germany.
  • 10 Department of Dermatology, Venereology and Allergology, University Hospital Essen, NCT West, Campus Essen, German Cancer Consortium, Partner Site Essen (DKTK) & University Alliance Ruhr, Research Center One Health, Essen, Germany.
  • 11 Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 12 TRON, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 13 Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 14 Department of Dermatology, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany. kramerda@uni-mainz.de.
  • 15 Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany. kramerda@uni-mainz.de.
PMID: 40562773 DOI: 10.1038/s41467-025-60929-5
Abstract

IκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ's function in solid Cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppresses CXCL9, Cxcl10, and Ccl5 expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8+ T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses.

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