EPIC1 reduces dsRNA biogenesis. Credit: Science Signaling (2025). DOI: 10.1126/scisignal.adr9131

Immunotherapy employs patients' own immune systems to fight cancer, and it has shown itself to be an effective treatment in many cases. However, some cancers, like triple-negative breast cancer (TNBC), show resistance to immunotherapy. This occurs when tumor cells find ways to evade immune detection—like suppressing immune signaling pathways. One such mechanism is the use of long noncoding RNAs (lncRNAs), which have been found to regulate cancer biology and immune evasion. These lncRNAs render immunotherapies, like the PD-1 inhibitor, pembrolizumab, ineffective.

The good news is that if these mechanisms of immunotherapy-resistance can be identified, scientists may be able to reverse or inactivate them. In a new study, published in Science Signaling, scientists focus on the lncRNA, EPIC1, and its interaction with histone methyltransferase, EZH2, a known contributor of tumor immune evasion in cancer cells.

According to the researchers, they sought to investigate the mechanism by which EPIC1 modulates immune function and determine how it regulates the expression of retroelements (REs)—mobile DNA sequences that produce double-stranded RNA when activated—and dsRNA accumulation in tumor cells.

The researchers found that EPIC1 suppresses the accumulation of cytoplasmic dsRNA and type I interferon (IFN) responses in multiple cancer cell lines, including breast cancer, prostate cancer, and pancreatic cancer. EPIC1 and EZH2 were also shown to work together to repress the expression of immunogenic REs, suggesting a shared pathway for immune evasion.

The study authors write, "Collectively, these results suggest that EPIC1 suppression promotes an antiviral-like type I IFN response with potential antitumor effects."

To test out the effect of EPIC1 knockdown, the researchers used "humanized mice"—mice with human immune systems implanted to mimic the effect of the mechanism in a human. Using these mouse models along with RNA interference to knock down EPIC1 in various cancer cell lines, they found that targeting EPIC1 enabled reduced tumor growth and increased T cell and inflammatory macrophage infiltration. This led to a significant improvement in the efficacy of pembrolizumab in TNBC.

"EPIC1 can be a potential therapeutic target in combination with immunotherapy. Coculture assays of T cells or monocytes with cancer cells showed that EPIC1 knockdown could significantly increase the therapeutic effect of pembrolizumab through antitumor T cell and macrophage activation, " the researchers write.

This is a promising result, offering hope for more effective treatments for aggressive cancers with limited options. However, the study authors note that these results still need to be tested out in human models and with other types of cancers to determine how best to improve immunotherapy outcomes in the future.

Written for you by our author Krystal Kasal, edited by Gaby Clark, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

More information: Dhamotharan Pattarayan et al, The lncRNA EPIC1 suppresses dsRNA-induced type I IFN signaling and is a therapeutic target to enhance TNBC response to PD-1 inhibition, Science Signaling (2025). DOI: 10.1126/scisignal.adr9131  Journal information: Science Signaling

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