Tumor transformation with entinostat, turning resistant cancers into receptive targets for immunotherapy.

Turning the Tide: How to Make Breast & Pancreatic Cancer Respond to Immunotherapy

Elliot Brynn in Health & Wellness August 2025 • 4 min read.

"New research reveals how a drug called entinostat can reprogram cancer cells to respond to treatments they were once resistant to."

Immunotherapy, particularly immune checkpoint inhibition (ICI), has transformed cancer treatment, especially for cancers easily recognized by the immune system. However, breast and pancreatic cancers, with their complex and suppressive tumor microenvironments (TMEs), remain challenging, showing low response rates to ICI. These tumors often recruit myeloid-derived suppressor cells (MDSCs), which hinder T-cell activation and infiltration, critical for successful immunotherapy.

A promising strategy involves epigenetic modulation to target MDSC trafficking and function, creating a TME that's more receptive to immune attack. This approach aims to make these stubborn tumors more responsive to ICI, boosting the chances of effective treatment.

New research explores using entinostat (ENT), a histone deacetylase inhibitor, in combination with ICI, such as anti-PD-1 and anti-CTLA-4. The results indicated significantly improved tumor-free survival in models of HER2/neu transgenic breast cancer and metastatic pancreatic cancer, offering hope for overcoming treatment resistance.

Reprogramming Immune Cells: How Entinostat Changes the Game

Tumor transformation with entinostat, turning resistant cancers into receptive targets for immunotherapy.

The study used mouse models to mimic breast and pancreatic cancers, employing flow cytometry, gene-expression profiling, and functional assays to deeply analyze tumor-infiltrating lymphocytes (TILs) and MDSCs. The goal was to understand how entinostat, when combined with checkpoint inhibition, affects these immune cell populations and their functions within the TME.

Researchers found that entinostat significantly reduced the suppressive activity of granulocytic MDSCs in the tumor microenvironment of both breast and pancreatic cancer models. Additionally, the combination therapy led to an increase in activated, granzyme-B-producing CD8+ T effector cells, which are crucial for killing cancer cells.

Reduced Suppression: Entinostat decreases the suppressive effects of granulocytic MDSCs, key cells that normally shut down the immune response in tumors.
T Cell Activation: The treatment boosts the activity of CD8+ T effector cells, which are essential for directly attacking and destroying cancer cells.
Gene Expression Changes: Both MDSCs and TILs showed significant changes in immune-related pathways, indicating a reprogramming of their functions.

Gene expression profiling further revealed that entinostat significantly alters the infiltration and function of innate immune cells. By modulating the tumor microenvironment, entinostat facilitates a more robust adaptive immune response, paving the way for checkpoint inhibitors to work more effectively. These findings provide a strong rationale for combination therapies in patients with traditionally immune-resistant cancers like breast and pancreatic cancer.

Hope for the Future: What This Means for Cancer Treatment

This research highlights the potential of entinostat to transform immune-resistant cancers into more manageable and treatable conditions. By altering the tumor microenvironment and enhancing the effectiveness of immune checkpoint inhibitors, entinostat opens new avenues for combination therapies.

These findings have significant implications for clinical trials and patient care, suggesting that combining epigenetic modulators like entinostat with immunotherapy could improve outcomes for those with breast and pancreatic cancers. Current clinical trials (NCT02453620 and NCT03250273) are underway to further explore combining entinostat with immunotherapeutic agents.

Ultimately, this approach aims to harness the body's immune system more effectively, providing new hope for patients with some of the most challenging cancers to treat. Further research and clinical application promise a future where even the most resistant tumors can be made vulnerable to the power of immunotherapy.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1158/2326-6066.cir-18-0070, Alternate LINK

Title: Entinostat Converts Immune-Resistant Breast And Pancreatic Cancers Into Checkpoint-Responsive Tumors By Reprogramming Tumor-Infiltrating Mdscs

Subject: Cancer Research

Journal: Cancer Immunology Research

Publisher: American Association for Cancer Research (AACR)

Authors: Brian J. Christmas, Christine I. Rafie, Alexander C. Hopkins, Blake A. Scott, Hayley S. Ma, Kayla A. Cruz, Skylar Woolman, Todd D. Armstrong, Roisin M. Connolly, Nilo A. Azad, Elizabeth M. Jaffee, Evanthia T. Roussos Torres

Published: 2018-12-01

Everything You Need To Know

What is immunotherapy and why is it important in cancer treatment?

Immunotherapy, particularly immune checkpoint inhibition (ICI), is a cancer treatment approach that leverages the body's immune system to fight cancer. While effective for some cancers, it often struggles against breast and pancreatic cancers due to their complex tumor microenvironments (TMEs). These TMEs are often filled with myeloid-derived suppressor cells (MDSCs), which suppress the immune response, hindering the effectiveness of ICI. Therefore, to improve the efficacy of ICI, strategies are needed to modulate the TME to make it more receptive to immune attack.

How does entinostat work to fight cancer?

Entinostat (ENT) is a histone deacetylase inhibitor that can change how the immune system interacts with cancer cells. The research shows that ENT, when combined with immune checkpoint inhibitors (ICI), improves outcomes in breast and pancreatic cancer models. ENT reduces the suppressive activity of granulocytic MDSCs, allowing the immune system, specifically CD8+ T effector cells, to function more effectively. This reprogramming of the tumor microenvironment (TME) makes the cancer more responsive to immunotherapy.

What are myeloid-derived suppressor cells (MDSCs) and what role do they play in cancer?

Myeloid-derived suppressor cells (MDSCs) are immune cells that suppress the immune system's ability to attack cancer. In breast and pancreatic cancers, MDSCs are abundant within the tumor microenvironment (TME) and hinder the activity of T cells, preventing them from killing cancer cells. Entinostat (ENT) works by reducing the suppressive effects of MDSCs, thereby enabling other immune cells, such as CD8+ T effector cells, to more effectively target and destroy cancer cells. By modulating MDSCs, ENT helps create a TME that is more receptive to immunotherapy.

What are CD8+ T effector cells and why are they important in this treatment approach?

CD8+ T effector cells are a type of immune cell crucial for killing cancer cells directly. When entinostat (ENT) is used in combination with immune checkpoint inhibitors (ICI), it boosts the activity of these cells. The study found that ENT treatment led to an increase in activated, granzyme-B-producing CD8+ T effector cells within the tumor microenvironment (TME). This increased activity is essential for enhancing the effectiveness of ICI, allowing the immune system to better recognize and eliminate cancer cells in breast and pancreatic cancers.

What is the tumor microenvironment (TME) and why is it significant in cancer treatment?

The tumor microenvironment (TME) refers to the complex environment surrounding a tumor, which includes various cells like immune cells (such as MDSCs and T cells), blood vessels, and signaling molecules. In breast and pancreatic cancers, the TME is often suppressive, filled with MDSCs that hinder the immune system's ability to fight cancer. Entinostat (ENT) alters the TME by reducing MDSC activity and promoting T cell activation. This modulation makes the TME more receptive to immunotherapy, enabling immune checkpoint inhibitors (ICI) to work more effectively and leading to improved outcomes in cancer treatment.