Data availability
Sequencing and proteomic data generated in this study are publicly available in the following MINSEQE-compliant repositories: Proteomic data are available in the PRIDE database (ID PXD065735) and in the MassIVE repository (ID PXD066359). Whole-exome sequencing data have been deposited in the Sequence Read Archive (SRA) (BioProject ID PRJNA1293554). TCR sequencing data are available in the Gene Expression Omnibus (GEO) under accession number GSE282715. Bulk RNA sequencing data are available in GEO under [GSE…
Data availability
Sequencing and proteomic data generated in this study are publicly available in the following MINSEQE-compliant repositories: Proteomic data are available in the PRIDE database (ID PXD065735) and in the MassIVE repository (ID PXD066359). Whole-exome sequencing data have been deposited in the Sequence Read Archive (SRA) (BioProject ID PRJNA1293554). TCR sequencing data are available in the Gene Expression Omnibus (GEO) under accession number GSE282715. Bulk RNA sequencing data are available in GEO under GSE283573 and GSE303491, and single-cell RNA sequencing data under GSE283827. Additional materials are available upon request from the corresponding authors. The single-cell RNA-seq data from Chan et al. 10 used for comparative analysis were accessed via Cell × Gene [https://cellxgene.cziscience.com/e/34deb33b-a50e-4993-a38b-1c0e5079c1c2.cxg]. RNA expression data from human SCLC cell lines were obtained from the GDSC-MGH-Sanger dataset accessed via CellMinerCDB [https://discover.nci.nih.gov/cellminercdb/]. The IMpower133 dataset was accessed from the European Genome-phenome Archive under the identifier EGAS50000000138 via https://ega-archive.org/ with the approval DA01145. These data were not generated in this study. The remaining data are available within the Article, Supplementary Information or Source Data file. Source data are provided with this paper.
References
Konig, K. et al. Implementation of amplicon parallel sequencing leads to improvement of diagnosis and therapy of lung cancer patients. J. Thorac. Oncol. 10, 1049–1057 (2015).
George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015).
Horn, L. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018).
Liu, S. V. et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J. Clin. Oncol. 39, 619–630 (2021).
Ko, J., Winslow, M. M. & Sage, J. Mechanisms of small cell lung cancer metastasis. EMBO Mol. Med. 13, e13122 (2021).
Ko, J. H. et al. Small cell lung cancer plasticity enables NFIB-independent metastasis. Cancer Res. 84, 226–240 (2024).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Marusic-Galesic, S., Stephany, D. A., Longo, D. L. & Kruisbeek, A. M. Development of CD4-CD8+ cytotoxic T cells requires interactions with class I MHC determinants. Nature 333, 180–183 (1988).
Nabet, B. Y. et al. Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade. Cancer Cell 42, 429–443.e4 (2024).
Chan, J. M. et al. Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer. Cancer Cell 39, 1479–1496.e18 (2021).
Edidin, M., Achilles, S., Zeff, R. & Wei, T. Probing the stability of class I major histocompatibility complex (MHC) molecules on the surface of human cells. Immunogenetics 46, 41–45 (1997).
Zevini, A., Olagnier, D. & Hiscott, J. Crosstalk between cytoplasmic RIG-I and STING sensing pathways. Trends Immunol. 38, 194–205 (2017).
Baccelli, I. et al. Mubritinib targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia. Cancer Cell 36, 84–99.e8 (2019).
Sen, T. et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 9, 646–661 (2019).
Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).
Poeck, H. et al. 5’-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat. Med. 14, 1256–1263 (2008).
Basit, A. et al. The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels. Exp. Mol. Med. 52, 643–657 (2020).
Fang, R. et al. MAVS activates TBK1 and IKKepsilon through TRAFs in NEMO dependent and independent manner. PLoS Pathog. 13, e1006720 (2017).
Yang, W. et al. Genomics of drug sensitivity in cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 41, D955–D961 (2013).
Holder, A. M. et al. Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours. Nat. Rev. Cancer 24, 498–512 (2024).
Meder, L. et al. Blocking the angiopoietin-2-dependent integrin beta-1 signaling axis abrogates small cell lung cancer invasion and metastasis. JCI Insight 9, e166402 (2024). 1.
Mok, T. S. K. et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393, 1819–1830 (2019).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Xie, M. et al. Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study. Mol. Cancer 23, 115 (2024).
Ott, P. A. et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J. Clin. Oncol. 35, 3823–3829 (2017).
Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).
Burr, M. L. et al. An evolutionarily conserved function of polycomb silences the MHC Class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell 36, 385–401.e8 (2019).
Hiatt, J. B. et al. Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T-cell killing. Clin. Cancer Res. 28, 4551–4564 (2022).
Nguyen, E. M. et al. Targeting lysine-specific demethylase 1 rescues major histocompatibility complex class I antigen presentation and overcomes programmed death-ligand 1 blockade resistance in SCLC. J. Thorac. Oncol. 17, 1014–1031 (2022).
Lim, J. S. et al. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature 545, 360–364 (2017).
Calbo, J. et al. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19, 244–256 (2011).
Augert, A. et al. Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition. Sci. Signal. 12, eaau2922 (2019). 1.
Roper, N. et al. Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer. Nat. Commun. 12, 3880 (2021).
Blees, A. et al. Structure of the human MHC-I peptide-loading complex. Nature 551, 525–528 (2017).
Brea, E. J. et al. Kinase regulation of human MHC Class I molecule expression on cancer cells. Cancer Immunol. Res. 4, 936–947 (2016).
Wu, S. et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat. Cell Biol. 21, 1027–1040 (2019).
Meuwissen, R. et al. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 4, 181–189 (2003).
Ibruli, O. et al. A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade. J. Cancer Res. Clin. Oncol. 150, 496 (2024).
Petrosius, V. et al. Exploration of cell state heterogeneity using single-cell proteomics through sensitivity-tailored data-independent acquisition. Nat. Commun. 14, 5910 (2023).
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
Plubell, D. L. et al. Extended multiplexing of tandem mass tags (TMT) labeling reveals age and high fat diet specific proteome changes in mouse epididymal adipose tissue. Mol. Cell Proteom. 16, 873–890 (2017).
Uniform manifold approximation and projection. Nat. Rev. Methods Primers 4, 83 (2024). 1.
Levine, J. H. et al. Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis. Cell 162, 184–187 (2015). 1.
Budczies, J. et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE 7, e51862 (2012).
Acknowledgements
Human lung cancer cell lines were kindly provided by Roman K. Thomas (Department of Translational Genomics, University of Cologne, Germany) and Reinhard Büttner (Institute for Pathology, University Hospital Cologne, Germany). We thank Renato Liguori (Bioinformatics and Computational Pathology, Friedrich-Alexander Universität Erlangen-Nürnberg, Germany) and Yussuf Hajjaj (Chair for Experimental Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg, Germany) for handling the IMpower133 data under DA01145, Theodoros Georgomanolis (Cologne Excellence Cluster on Aging and Aging-Associated Diseases, University of Cologne, Germany) for his bioinformatics support regarding TCR sequencing, Jaewon Kwak (Institute for Pathology, Faculty of Medicine and University Hospital of Cologne, Germany) for the support in patient data management, Johannes Lindemeyer (Department of Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital of Cologne, Germany) and the Core Facility Experimental and Preclinical Imaging Cologne (University of Cologne, Faculty of Medicine and University Hospital Cologne, Germany) and Julian Kallinowski (Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Germany) for support with small animal imaging. We thank Kerstin Wennhold (Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, Germany) for sharing the T cell OVA cytotoxicity assay protocol. We thank the CECAD Proteomics Core Facility and the DKTK for proteomics analysis. Proteomics data acquisition at the University of Cologne was performed on an instrument granted by the Deutsche Forschungsgemeinschaft under grant INST 216/1163-1 FUGG. We thank Martine Pape and Marion Bodach of DKTK proteomics platform Frankfurt for their excellent technical assistance. We thank the Cologne Center for Genomics (CCG) for performing whole-exome and RNA sequencing and their support in data generation. The figures were created with BioRender.com: Meder, L. (2025) https://BioRender.com/z2ehzfh, Meder, L. (2025) https://BioRender.com/su67ybp, Meder, L. (2025) https://BioRender.com/4u5k5v3, Meder, L. (2025) https://BioRender.com/w6kb2vb, Meder, L. (2025) https://BioRender.com/dwd4xgv, Meder, L. (2025) https://BioRender.com/3wkefcf, Meder, L. (2025) https://BioRender.com/x5oxh7c, Meder, L. (2025) https://BioRender.com/bxcwg6c, Meder, L. (2025) https://BioRender.com/vkn5pfz, Meder, L. (2025) https://BioRender.com/y4lktuu, Meder, L. (2025) https://BioRender.com/eyhkfjh, Meder, L. (2025) https://BioRender.com/a7q733t. This work was supported by Wilhelm Sander Stiftung, Grant No.: R2024.171.1 (RTU), Interdisciplinary Center for Clinical Research of the Faculty of Medicine of the Friedrich-Alexander University Erlangen-Nürnberg Grant No.: 29133011 (LM), German federal state North Rhine Westphalia; Grant No.: 1411ng005 (RTU); Grant No.: LS-1-1-030a (HCR); the CANTAR network Grant No.: NW21-062B funded through the program “ Netzwerke 2021”, an initiative of the Ministry of Culture and Science of the State of North Rhine Westphalia, Germany (JB), German Cancer Aid; Grant No.: 70113009 (RTU); Grant No.: 111724 (HCR); Grant No.: 70113307 (LM; DS; JB; FB), Grant No.: 70114593 (KN) Fritz-Thyssen Foundation; Grant No.: 10.21.1.026MN (LM), German Research Foundation; Grant No.: UL379/1-1 (RTU); CRC-1399/A01/C02 (HCR; FB), CRC-1399/ project ID 413326622 (JB), CRC1310/project ID 325931972 (CK, FK, JB), CRC-1530/B05 (RTU), GRK 3110/1 (KN; JW; RB; RTU), CRC-1530/INF (NA), Grant No.: 497777992 (NA), Else Kröner-Fresenius Foundation; Grant No.: EKFS-2014-A06 (HCR), Memorial Grant 2018_EKMS.35 (JB), and MD Research Stipend of the Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Germany (DS), Ministry of Culture and Science of the German state of North Rhine-Westphalia as part of the support programme Cancer Center Cologne Essen (NA).
Funding
Open Access funding enabled and organized by Projekt DEAL.
Author information
Author notes
These authors contributed equally: Lydia Meder, Charlotte I. Orschel, Cyrielle L. Bouchez.
Authors and Affiliations
Chair of Experimental Medicine 1, Faculty of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
Lydia Meder & Ilayda G. Kocak 1.
Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Universitätsklinikum Erlangen, Erlangen, Germany
Lydia Meder 1.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Cologne, Germany
Charlotte I. Orschel, Cyrielle L. Bouchez, Rahil Gholamipoorfard, Claudia V. Orschel, David Stahl, Mirjam Koker, Marieke Nill, Jürgen Wolf, Filippo Beleggia, Nima Abedpour & Roland T. Ullrich 1.
Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
Charlotte I. Orschel, Cyrielle L. Bouchez, David Stahl, Mirjam Koker, Marieke Nill, Reinhard Büttner, Johannes Brägelmann & Roland T. Ullrich 1.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Mildred Scheel School of Oncology, Cologne, Germany
Charlotte I. Orschel, Cyrielle L. Bouchez, Claudia V. Orschel, David Stahl, Filippo Beleggia, Johannes Brägelmann & Roland T. Ullrich 1.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany
Rahil Gholamipoorfard, Filippo Beleggia, Johannes Brägelmann & Nima Abedpour 1.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Virology, Laboratory of Experimental Immunology, Cologne, Germany
Christoph Kreer, Leon Ullrich & Florian Klein 1.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
Ka-Won Noh, Xinlei Zhao, Marie-Lisa Eich, Alexandra Florin & Reinhard Büttner 1.
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany
Björn Häupl, Josefine Jakob & Thomas Oellerich 1.
German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Björn Häupl, Josefine Jakob & Thomas Oellerich 1.
Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany
Björn Häupl, Josefine Jakob & Thomas Oellerich 1.
German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Germany, Frankfurt am Main, Germany
Björn Häupl & Thomas Oellerich 1.
Institute of Pathology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humbolt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
Marie-Lisa Eich 1.
Core Facility Experimental and Preclinical Imaging Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
Holger Grüll 1.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Diagnostic and Interventional Radiology, Cologne, Germany
Holger Grüll 1.
University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany
Jürgen Wolf, Reinhard Büttner & Roland T. Ullrich 1.
Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital of Bonn, Bonn, Germany
Johannes Brägelmann 1.
Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, German Cancer Consortium (DKTK), Essen, Germany
H. Christian Reinhardt 1.
Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Nima Abedpour
Authors
- Lydia Meder
- Charlotte I. Orschel
- Cyrielle L. Bouchez
- Rahil Gholamipoorfard
- Claudia V. Orschel
- David Stahl
- Christoph Kreer
- Mirjam Koker
- Marieke Nill
- Ilayda G. Kocak
- Ka-Won Noh
- Xinlei Zhao
- Leon Ullrich
- Björn Häupl
- Josefine Jakob
- Marie-Lisa Eich
- Alexandra Florin
- Holger Grüll
- Jürgen Wolf
- Filippo Beleggia
- Reinhard Büttner
- Thomas Oellerich
- Florian Klein
- Johannes Brägelmann
- H. Christian Reinhardt
- Nima Abedpour
- Roland T. Ullrich
Contributions
Conceptualization: L.M., H.C.R., N.A., R.T.U. Methodology: L.M., C.I.O., C.L.B., R.G., D.S., C.K., J.W., F.B., R.B., T.O., F.K., J.B., H.C.R., N.A., R.T.U. Investigation: L.M., C.I.O., C.L.B., R.G., C.V.O., D.S., M.K., M.N., I.G.K., K.N., X.Z., L.U., B.H., J.J., M.E., A.F., H.G., F.B., R.B., T.O., N.A., R.T.U. Visualization: L.M., C.I.O., C.L.B., M.K., D.S., R.G., N.A. Funding acquisition: L.M., J.B., D.S., F.B., H.C.R., R.T.U. Project administration: L.M., R.T.U. Supervision: L.M., R.T.U. Writing— original draft: L-.M., C.I.O., C.L.B., R.G., C.K., R.T.U. Writing—review & editing: L-.M., C.I.O., C.L.B., R.G., C.V.O., D.S., C.K., M.K., M.N., I.G.K., K.N., X.Z., L.U., B.H., J.J., M.E., A.F., H.G., J.W., F.B., R.B., T.O., F.K., J.B., H.C.R., N.A., R.T.U.
Corresponding authors
Correspondence to Lydia Meder or Roland T. Ullrich.
Ethics declarations
Competing interests
H.C.R. received consulting and lecture fees from Abbvie, Roche, KinSea, Vitis, Cerus, Lilly, Novartis, Takeda, AstraZeneca, Vertex, and Merck. H.C.R. received research funding from AstraZeneca and Gilead Pharmaceuticals. H.C.R. is a co-founder of CDL Therapeutics GmbH. J.B. has received research funding from Bayer and travel grants by Merck and Bicycle Therapeutics outside of the submitted work. T.O. received research funding from Gilead and Merck KGaA, is a consultant/received honoraria for/from Beigene, Roche, Janssen, Merck KGaA, Gilead, Kronos Bio and Abbvie (all not related to this work). The remaining authors declare no conflicting interests. J.B. has received research funding from Bayer outside of the submitted work. The remaining authors declare no competing interests.
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Cite this article
Meder, L., Orschel, C.I., Bouchez, C.L. et al. ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66800-x
Received: 13 November 2024
Accepted: 14 November 2025
Published: 09 December 2025
DOI: https://doi.org/10.1038/s41467-025-66800-x