Epigenetic Regulation of Immune Responses in Endocrine-Related Cancers and Its Role in Immunotherapy
by
, , , and
Evren M. Akyuz
1,2
,
Meryem Gultekin
2,3,
Judith M. Ramage
2,3,
Ian Spendlove
2,3,
Andrew M. Jackson
2,3,
Jason Adhikaree
2,3 and
Anna A. Malecka
1,2,* 1
School of Veterinary Medicine and Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham LE12 5RD, UK
2
Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
3
School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2UH, UK
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(20), 3342; https://doi.org/10.3390/cancers17203342
Submission received: 27 August 2025
/
Revised: 3 October 2025
/
Accepted: 10 October 2025
/
Published: 16 October 2025
(This article belongs to the Special Issue Epigenetics in Endocrine-Related Cancer)
Simple Summary
Endocrine-related cancers often acquire resistance to current therapies. New therapeutic approaches such as epigenetic modulation and immunotherapy, while promising, so far have delivered little benefit. Recent research suggests that epigenetic mechanisms are key in the regulation of anti-cancer immune responses and play an important role in the therapeutic resistance of endocrine-related cancers. This review provides an overview of the immune landscape of endocrine-related cancers, including breast, prostate, ovarian and thyroid. We discuss epigenetic modulators of anti-cancer immune responses and current clinical trials combining immunotherapy with epigenetic modulation, with the aim of invigorating anti-cancer immune responses.
Abstract
Endocrine-related cancers are commonly diagnosed worldwide and are a major cause of cancer-related deaths. While current therapies are effective at earlier stages, they often fail in more advanced or recurring tumors due to the development of primary and secondary resistance. Therefore, new therapeutic approaches are urgently needed. In recent years, new therapeutic avenues, namely immunotherapy and epigenetic modulation, have been successfully explored in multiple cancer types. However, this success has not been observed in endocrine-related cancers. These tumors are considered immunologically cold, characterized by a low immunogenicity, scarce infiltration by immune cells, and highly immunosuppressive environment rendering them resistant to immunotherapy. Recent studies demonstrated the ability of epigenetic agents to simultaneously alter the behavior of tumor and immune cells, giving premise to combination approaches using epigenetic modulation to prime cancer for immunotherapy. This review provides an overview of the immune landscape of endocrine-related cancers and its main epigenetic regulators. We discuss current clinical trials investigating the effect of combination endocrine-related immunotherapy and their challenges to successfully treat endocrine-related cancers.
