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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI193153

Estrogen Receptor signaling drives immune evasion and immunotherapy resistance in HR+ breast cancer

José Ángel Palomeque,1 Gabriel Serra-Mir,1 Sandra Blasco-Benito,1 Helena Brunel,1 Pau Torren-Duran,1 Iván Pérez-Núñez,1 Chiara Cannatá,1 Laura Comerma,2 Silvia Menendez,1 Sonia Servitja,1 Tamara Martos,3 Maria Castro,3 Rodrigo L. Borges,4 Joanna I. Lopez-Velazco,5 Sara Manzano,5 Santiago Duro-Sánchez,1 Joaquin Arribas,1 Maria M. Caffarel,5 Ander Urruticoechea,6 Jose A. Seoane,7 Lluis Morey,4 Joan Albanell,1 and Toni Celià-Terrassa1

1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

Find articles by Palomeque, J. in: PubMed | Google Scholar

1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

Find articles by Menendez, S. in: PubMed | Google Scholar

1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

Find articles by Martos, T. in: PubMed | Google Scholar

1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

Find articles by Morey, L. in: PubMed | Google Scholar |

1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

Find articles by Albanell, J. in: PubMed | Google Scholar

1Cancer Research Program, Hospital del Mar Research Institute (HMRI), Barcelona, Spain

2Pathology Department, Hospital del Mar, Barcelona, Spain

3Medical Oncology Department, Hospital del Mar, Barcelona, Spain

4Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States of America

5Biogipuzkoa (Previously Known Biodonostia) Health Research Institute, San Sebastian, Spain

6IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

7Cancer Computational Biology Group, Vall d’Hebron Institue of Oncology, Barcelona, Spain

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Published November 25, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI193153.
Copyright © 2025, Palomeque et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 25, 2025 - Version history
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Abstract

Hormone Receptor positive (HR+) breast cancers (BC) are typically “immune-cold” poorly immune infiltrated tumors that do not respond to immune-checkpoint blockade (ICB) therapies. Using clinical data, we report that estrogen receptor (ERα) signaling associates with immunosuppressive pathways and lack of response to ICB in HR+ patients. In this study, we validate ER-mediated immunosuppression by engineering and modulating ER in preclinical models in vitro, in vivo and ex vivo. Mechanistically, we found that ERα hijacks LCOR, a nuclear receptor corepressor, thereby preventing LCOR’s function in the induction of tumor immunogenicity and immune infiltration, which is normally observed in the absence of ERα, such as in ER-negative BC. In HR+BC, we demonstrate that the molecular disruption of LCOR and ERα interaction using anti-ER therapies or using a mutant of the LCOR nuclear-receptor binding domain (LSKLL into LSKAA) that does not interact with ERα, restores LCOR’s immunogenic functions. Remarkably, the LCOR-ERα disruption converts HR+BC immune-cold tumors into immune-hot tumors responsive to ICB by increased antigen presentation machinery (APM) expression, immune infiltration, T cell recognition and mediated killing. In conclusion, ERα inhibition and the disruption of LCOR to ERα represent a novel therapeutic strategy and an opportunity to elicit immunotherapeutic benefit in HR+BC patients.

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