Epigenetic Regulation of Immune Responses in Endocrine-Related Cancers and Its Role in Immunotherapy

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.

Keywords: breast cancer; epi-drugs; epigenetics; immunology; immunotherapy; ovarian cancer; prostate cancer; thyroid cancer.

Figure 1

Immune Evasion. Cancers escape elimination by the immune system by evading recognition, selectively excluding immune cells from TME and actively inhibiting immune responses. Created in BioRender. Malecka, A.A. (2025) https://BioRender.com/p3ghanv (accessed on 1 October 2025).

Figure 2

Viral Mimicry. DNMT and LSD1 activity suppresses endogenous retrovirus (ERV) expression. Pharmacological inhibition using DNMTi and LSD1i restores ERV expression, leading to mRNA translation at the ribosome and production of tumor-specific antigens (TSAs). These TSAs are presented on MHC class I molecules for recognition by T cells via TCR. ERV expression also generates double-stranded RNA (dsRNA), which accumulates in the cytoplasm and activates canonical interferon (IFN) signaling through endosomal TLR3 or cytosolic MDA5, ultimately inducing IFN cytokine secretion. Created in BioRender. Malecka, A.A. (2025) https://BioRender.com/ujcazna (accessed on 1 October 2025).