ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer
Small cell lung cancer (SCLC) is characterized by its highly aggressive phenotype and dismal outcome. Despite the benefit of adding immune checkpoint blockade to standard chemotherapy, tumors acquire the ability to evade immunosurveillance and develop resistance. To investigate these underlying mechanisms, we perform high-dimensional profiling of human and murine SCLC specimens. In matched primary and metastatic human samples, we observe MHC-I loss in metastases, highlighting its role in immune evasion. Correspondingly, silencing MHC-I in SCLC cells drastically reduces immune infiltration and promotes metastasis in mice. Using mass spectrometry and phospho-tyrosine kinase analyses, we identify ERBB2 signaling as a suppressor of MHC-I and driver of immune-modulatory transcripts. Mechanistically, genetic and pharmacologic blockade of ERBB2 induces MHC-I in a STING-dependent manner and prevents immune evasion in autochthonous murine SCLC. Strikingly, combining ERBB2 inhibition with anti-PD-1 elicits profound synergistic responses in preclinical models, suggesting this combination for future clinical trials in SCLC patients.
Authors
- Ivo Kocák
- Reinhard Büttner (ORCID: https://orcid.org/0000-0001-8806-4786)
- Marie‐Lisa Eich (ORCID: https://orcid.org/0000-0002-8601-4598)
- Thomas Oellerich (ORCID: https://orcid.org/0000-0001-6570-6125)
- Leon Ullrich (ORCID: https://orcid.org/0000-0002-4358-0717)
- Juergen Wolf (ORCID: https://orcid.org/0000-0001-8833-8812)
- Hans Christian Reinhardt (ORCID: https://orcid.org/0000-0001-5706-9349)
- Filippo Beleggia (ORCID: https://orcid.org/0000-0003-0234-7094)
- Nima Abedpour (ORCID: https://orcid.org/0000-0002-2933-8035)
- Christoph Kreer (ORCID: https://orcid.org/0000-0002-9140-9850)
- Cyrielle Bouchez (ORCID: https://orcid.org/0000-0002-5318-3547)
- Xinlei Zhao (ORCID: https://orcid.org/0000-0002-6709-2961)
- Josefine Jakob
- Holger Grüll (ORCID: https://orcid.org/0000-0002-0993-9300)
- Roland T. Ullrich
- Lydia Meder (ORCID: https://orcid.org/0000-0002-9547-5812)
- Björn Häupl (ORCID: https://orcid.org/0009-0000-9445-9565)
- Marieke Nill
- Alexandra Florin (ORCID: https://orcid.org/0000-0002-2330-4176)
- Ka‐Won Noh (ORCID: https://orcid.org/0000-0002-0041-9560)
- Florian Klein (ORCID: https://orcid.org/0000-0003-1376-1792)
- Johannes Brägelmann (ORCID: https://orcid.org/0000-0002-1306-2169)
- Mirjam Koker
- Rahil Gholamipoorfard
- David Stahl
- Charlotte Isabelle Orschel
Institutions
- Goethe University Frankfurt (DE)
- German Cancer Research Center (DE)
- University of Cologne (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Heidelberg University (DE)
- University Hospital Bonn (DE)
- Humboldt-Universität zu Berlin (DE)
- Düsseldorf University Hospital (DE)
- Essen University Hospital (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Comprehensive Cancer Center Erlangen (DE)
- University Hospital Cologne (DE)
- Frankfurt Cancer Institute (DE)
- West German Heart and Vascular Center Essen (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1038/s41467-025-66800-x
- Citations
- 3
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Deutsche Forschungsgemeinschaft
- Universität zu Köln
- Deutschen Konsortium für Translationale Krebsforschung
- Universitätsklinikum Köln