New Advances in Breast Cancer Treatment: Targeting EPIC1 to Overcome Immunotherapy Resistance

Recent research has highlighted a promising approach to overcoming resistance to immunotherapy in breast cancer, especially in aggressive forms like triple-negative breast cancer (TNBC). Immunotherapy utilizes the patient’s own immune system to combat cancer cells, but some tumors develop mechanisms to evade immune detection. One such mechanism involves long noncoding RNAs (lncRNAs), which play a role in regulating tumor behavior and immune evasion. These lncRNAs can render treatments like PD-1 inhibitors, for example pembrolizumab, less effective.

A groundbreaking study published in Science Signaling focuses on the lncRNA EPIC1 and its interaction with the histone-modifying enzyme EZH2, both of which contribute to immune evasion by cancer cells. The researchers investigated how EPIC1 influences immune signaling pathways and its role in regulating retroelements—mobile DNA sequences that trigger the production of double-stranded RNA (dsRNA)—and the accumulation of dsRNA within tumor cells.

The findings revealed that EPIC1 suppresses the buildup of cytoplasmic dsRNA and dampens type I interferon (IFN) responses in several cancer cell types, including breast, prostate, and pancreatic cancers. EPIC1 collaborates with EZH2 to repress immunogenic retroelements, thereby helping cancer cells evade immune detection. When EPIC1 levels were reduced, there was an induction of an antiviral-like immune response characterized by increased IFN signaling, which could enhance the body's ability to target tumors.

To evaluate potential therapeutic effects, scientists used 'humanized mice'—models with human immune systems—and applied RNA interference to knock down EPIC1 expression in various cancer cell lines. This strategy resulted in decreased tumor growth and attracted more immune cells such as T cells and inflammatory macrophages to the tumor environment. Notably, combining EPIC1 suppression with the PD-1 inhibitor pembrolizumab significantly improved treatment efficacy in TNBC models.

These insights suggest that targeting EPIC1 may restore immune responses and improve immunotherapy outcomes. The research indicates that EPIC1 could be a valuable therapeutic target, especially when combined with existing immune checkpoint therapies. However, further studies are necessary to validate these findings in human clinical trials and across different cancer types to better understand how this approach can be integrated into cancer treatment regimens.

Source: https://medicalxpress.com/news/2025-08-scientists-reverse-immunotherapy-resistance-suppressing.html