Bold claim: a new strategy could finally make the most common type of breast cancer—estrogen receptor–positive (ER+) or luminal breast cancer—responsive to immunotherapy. A team from the Hospital del Mar Research Institute reports a pivotal advance that could change treatment for a disease that accounts for about 70% of breast cancer cases and, despite good therapies, remains the leading cause of mortality in total breast cancer figures. Immunotherapy has largely not worked for ER+ tumors, except in a small subgroup with low estrogen receptor levels. The findings appear in The Journal of Clinical Investigation and come from Dr. Toni Celià-Terrassa’s Cancer Stem Cells and Metastasis Dynamics Laboratory. The work was supported by Ausonia through the Spanish Association Against Cancer.
Key insight: the estrogen receptor helps the tumor hide from the immune system. By reanalyzing public data from multiple clinical trials, the researchers showed that ER signaling limits immune cell infiltration and blunts immunotherapy effectiveness. Conversely, blocking the estrogen receptor frees the LCOR molecule and boosts interferon-driven signals, both of which support antigen presentation on the tumor cell surface and make the cancer more detectable to immune cells.
To test this idea, the team built preclinical animal models that confirmed the protective mechanism. They discovered that LCOR, which has been shown in other breast cancer models (notably triple-negative) to boost immunotherapy responses, is ordinarily trapped by the estrogen receptor and cannot perform its job. “The estrogen receptor sequesters LCOR and prevents it from activating the antigen-presenting machinery, conditioning its function and not allowing the tumor to become ‘visible,’” explains Dr. Toni Celià-Terrassa.
Two preclinical strategies were explored to counteract this effect. First, the researchers combined LCOR with immunotherapy and concurrent endocrine (hormonal) therapy, a standard approach for ER+ breast cancer. Second, they engineered a modified LCOR variant (LSKAA) that resists sequestration by the estrogen receptor. Under typical conditions, estrogen signaling dominates in ER+ tumors and blocks LCOR. By interrupting this signaling with antiestrogen therapy, LCOR can activate antigen presentation and unlock the path for immunotherapy. The engineered LCOR avoids estrogen receptor interference and strengthens the antigen-presenting process necessary for immune attack.
Ongoing work and future directions: the Hospital del Mar RNA therapy generation laboratory is using this approach to develop modified LCOR therapies that work in concert with immunotherapy without being trapped by the estrogen receptor. Additionally, a new spin-off, VIOLET Pharmaceuticals, is pursuing these therapeutic avenues.
Commentary from the field: Dr. Joan Albanell, head of the Medical Oncology Service at Hospital del Mar and director of the Cancer Research Program there, states that this study opens a promising new route to sensitize ER+ breast cancer to immunotherapy. The aim is to translate these findings into clinical trials, exploring modified LCOR therapies for patients whose tumors express estrogen receptors and for whom immunotherapy has so far shown limited efficacy.
Source:
Palomeque, J. Á., et al. (2025). Estrogen Receptor signaling drives immune evasion and immunotherapy resistance in HR+ breast cancer. Journal of Clinical Investigation. doi: 10.1172/jci193153. https://www.jci.org/articles/view/193153
Suggested reading and notes:
- The study emphasizes ER signaling as a driver of immune evasion in ER+ breast cancer.
- The LCOR axis emerges as a key regulator of antigen presentation and immunotherapy responsiveness.
- The two-pronged approach—combining LCOR with endocrine therapy or using a resistant LCOR variant—offers a blueprint for future trials.
Important reminder: while this summary conveys the study’s goals and implications, it does not replace medical advice. Patients should consult healthcare professionals for guidance tailored to their circumstances. The information here reflects published research and ongoing investigations, not established clinical recommendations.
What do you think: should future discussions on ER+ breast cancer focus more on combining targeted hormone therapies with immunotherapy, or should emphasis shift toward engineering immune-visibility tools like modified LCOR? Share your thoughts and questions in the comments.
