Estrogen receptor signaling drives immune evasion and immunotherapy resistance in HR+ breast cancer
Hormone receptor-positive (HR+) breast cancers (BCs) 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 α (ERα) signaling was associated with immunosuppressive pathways and a lack of response to ICB in patients with HR+ BC. In this study, we validated ER-mediated immunosuppression by engineering and modulating the ER in preclinical models in vitro, in vivo, and ex vivo. Mechanistically, we found that ERα hijacked 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- 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, restored the immunogenic functions of LCOR. Remarkably, the LCOR-ERα disruption converted HR+ BC immune-cold tumors into immune-hot tumors responsive to ICB by increased antigen presentation machinery expression, immune infiltration, T cell recognition, and T cell-mediated killing. In conclusion, ERα inhibition and the disruption of LCOR-ERα interaction represent a therapeutic strategy and an opportunity to elicit immunotherapeutic benefit in patients with HR+ BC.
Authors
- Chiara Cannatá (ORCID: https://orcid.org/0000-0003-4807-4669)
- Sara Manzano (ORCID: https://orcid.org/0000-0002-0052-511X)
- Héléna Brunel (ORCID: https://orcid.org/0000-0002-1036-7928)
- José A. Seoane (ORCID: https://orcid.org/0000-0002-3856-9177)
- María M. Caffarel (ORCID: https://orcid.org/0000-0002-7442-6827)
- Laura Comerma (ORCID: https://orcid.org/0000-0002-0249-4636)
- Tamara Martos
- Joan Albanell (ORCID: https://orcid.org/0000-0003-1239-4580)
- Lluís Morey (ORCID: https://orcid.org/0000-0001-9851-4066)
- María Castro (ORCID: https://orcid.org/0000-0001-8941-5795)
- Sílvia Menéndez (ORCID: https://orcid.org/0000-0002-9116-8743)
- Toni Celià-Terrassa (ORCID: https://orcid.org/0000-0002-0615-8744)
- Santiago Duro‐Sánchez (ORCID: https://orcid.org/0000-0002-3829-7562)
- Joanna I. López-Velazco (ORCID: https://orcid.org/0000-0001-5620-6495)
- Sonia Servitja
- Sandra Blasco-Benito (ORCID: https://orcid.org/0000-0002-6714-2340)
- Iván Pérez-Núñez (ORCID: https://orcid.org/0000-0002-2907-1991)
- Joaquı́n Arribas (ORCID: https://orcid.org/0000-0002-0504-0664)
- Ander Urruticoechea (ORCID: https://orcid.org/0000-0003-0359-3641)
- José Ángel Palomeque
- Gabriel Serra-Mir (ORCID: https://orcid.org/0000-0003-1140-8063)
- Rodrigo L. Borges
- Pau Torren-Duran
Institutions
- Ikerbasque (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- University of Miami (US)
- Universitat Pompeu Fabra (ES)
- Instituto de Salud Carlos III (ES)
- Biogipuzkoa Health Research Institute (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Hospital Del Mar (ES)
- Onkologikoa (ES)
- Sylvester Comprehensive Cancer Center (US)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Vall d'Hebron Institute of Oncology (ES)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1172/jci193153
- Citations
- 1
- Primary Topic
- Breast Cancer Treatment Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Breast Cancer Research Foundation
- “la Caixa” Foundation
- European Commission
- Generalitat de Catalunya
- Banco Bilbao Vizcaya Argentaria
- Sociedad Española de Oncología Médica
- Centro de Investigación Biomédica en Red de Cáncer
- National Institutes of Health
- Instituto de Salud Carlos III
- National Cancer Institute
- National Institute of General Medical Sciences