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

Antonia Kolb, Ana-Marija Kulis-Mandic, Matthias Klein, Anna Stastny, Maximilian Haist, Vanessa Votteler, Beate Weidenthaler-Barth, Tobias Sinnberg, Antje Sucker, Gabriele Allies, Lea Jessica Albrecht, Alpaslan Tasdogan, Andrea Tuettenberg, Matthias M. Gaida, Carsten Deppermann, Henner Stege, Dirk Schadendorf, Stephan Grabbe, Klaus Schulze-Osthoff and Daniela Kramer ()
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Antonia Kolb: University Medical Center of the Johannes Gutenberg University of Mainz
Ana-Marija Kulis-Mandic: University Medical Center of the Johannes Gutenberg University of Mainz
Matthias Klein: University Medical Center of the Johannes Gutenberg University Mainz
Anna Stastny: University Medical Center of the Johannes Gutenberg University of Mainz
Maximilian Haist: University Medical Center of the Johannes Gutenberg University of Mainz
Vanessa Votteler: German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung) and German Cancer Research Center (Deutsches Krebsforschungszentrum)
Beate Weidenthaler-Barth: University Medical Center of the Johannes Gutenberg University of Mainz
Tobias Sinnberg: Eberhard Karls University Hospital Tübingen
Antje Sucker: Research Center One Health
Gabriele Allies: Research Center One Health
Lea Jessica Albrecht: Research Center One Health
Alpaslan Tasdogan: Research Center One Health
Andrea Tuettenberg: University Medical Center of the Johannes Gutenberg University of Mainz
Matthias M. Gaida: University Medical Center of the Johannes Gutenberg University of Mainz
Carsten Deppermann: University Medical Center of the Johannes Gutenberg University of Mainz
Henner Stege: University Medical Center of the Johannes Gutenberg University of Mainz
Dirk Schadendorf: Research Center One Health
Stephan Grabbe: University Medical Center of the Johannes Gutenberg University of Mainz
Klaus Schulze-Osthoff: German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung) and German Cancer Research Center (Deutsches Krebsforschungszentrum)
Daniela Kramer: University Medical Center of the Johannes Gutenberg University of Mainz

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60929-5

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