Fahri Saatçioğlu and His Team's Discovery That Makes Prostate Cancer Sensitive to Immunotherapy

The annual number of new prostate cancer cases is expected to rise from 1.4 million in 2020 to 2.9 million by 2040, according to projections. Changes in age structure and increasing life expectancy are driving the rise in this disease, making prostate cancer one of the most important issues in men's health. Most prostate cancers are now diagnosed at an early stage, and many treatment options are available. However, immunotherapies, which have revolutionized cancer treatment, have so far shown no meaningful effect in prostate cancer. Yet a discovery by one of the field's leading scientists, Prof. Fahri Saatçioğlu , and his team, on which they have worked for 15 years, offers considerable hope of making prostate cancer more sensitive to immunotherapy.

A New Horizon in Prostate Cancer Treatment

Professor Fahri Saatçioğlu, who works in Norway, has attracted the scientific community's attention with an innovative approach to treating prostate cancer. In a study published in 2019, he showed that it might be possible to inhibit tumor growth by blocking a signaling pathway called IRE1α in prostate cancer cells. The inhibitor used in the study, MKC8866 , could suppress tumor development by blocking the cancer cells' stress response. A human clinical trial of this inhibitor is now ongoing. 

However, Saatçioğlu and his team took their research further, evaluating the effect of IRE1α inhibition in prostate cancer treatment from a broader perspective. Their new study, published on October 15, 2024, in Nature Communications , shows that targeting IRE1α restructures the tumor microenvironment (TME) , strengthening the immune system's fight against the tumor. This discovery is an important development toward making immunologically “cold” tumors that are less readily recognized by the immune system, such as prostate cancer, more sensitive to immunotherapy.

What Is IRE1α, and What Is Its Role in Prostate Cancer?

The intracellular endoplasmic reticulum (ER) performs critical functions such as correct protein folding, processing, and distribution. Stress in the ER activates a defense mechanism known as the unfolded protein response (UPR). One of the main components of the UPR pathway, IRE1α, becomes activated in cancer cells and supports tumor development. This pathway allows cancer cells to survive even under extreme stress while making it harder for the immune system to recognize them.

The findings showed that inhibiting IRE1α in prostate cancer cells makes it easier for the immune system to recognize them and, in particular, prevents immunosuppressive cells such as tumor-associated macrophages (TAM) and regulatory T cells (Treg) from accumulating in the tumor microenvironment. This enhances the effect of immune cells against the tumor, making it possible to control prostate cancer growth.

A schematic summary of the study's main findings is shown below:

Figure Explanation: Activation of IRE1α in cancer cells suppresses interferon (IFN) responses and promotes the accumulation of immunosuppressive cells, such as TAMs (tumor-associated macrophages) and Tregs (regulatory T cells), in the tumor microenvironment (TME). This prevents an effective antitumor immune response and leads to tumor progression. Genetic targeting of IRE1α in cancer cells or combination treatment (MKC8866 + anti-PD-1) increases IFN responses in antigen-presenting cells (such as TAMs and DCs) and reduces the number of immunosuppressive cells in the TME. This facilitates a strong antitumor immune response and effectively inhibits tumor growth.

Study Findings: Reducing Tumor Growth by Targeting IRE1α

Experiments in mouse models showed that IRE1α inhibition significantly reduced tumor growth. In the study, MKC8866 , a small-molecule inhibitor, was used to inactivate IRE1α, leading to substantial shrinkage of prostate cancer tumors. Immune pathways such as interferon responses were also activated, and the density of CD8+ T cells and NK cells, which play a critical role in fighting tumors, increased.

Study Findings:

• A 50-75% reduction in the number of tumor-associated macrophages (TAMs) was achieved.
• The density of CD8+ T cells and NK cells increased significantly.
• Increased Immunogenic Response: IRE1α inhibition contributed to enhanced interferon responses and the accumulation of immune cells at the tumor site.

Combining IRE1α Inhibition with Immune Checkpoint Inhibitors (Immunotherapies)

In cancer treatment, immunotherapies such as immune checkpoint inhibitors have produced promising results in many cancers, but their effects remain limited in cancers poorly recognized by the immune system, such as prostate cancer. In this study, combining MKC8866 with an anti-PD-1 immune checkpoint inhibitor caused dramatic changes in the tumor microenvironment and significantly slowed tumor growth. This combination has the potential to transform prostate cancer into a “hotter” tumor environment that the immune system can target.

Effects of Combination Treatment:

• Significant Reduction in Tumor Growth: Combination treatment with anti-PD-1 therapy and MKC8866 stopped tumor growth, showing a much greater effect than either treatment alone.
• Increased Immune Cell Density: The combination increased the density of CD8+ T cells and NK cells in the tumor microenvironment, enabling the immune system to fight the tumor more strongly.
• Reprogramming the Tumor Microenvironment: The combination significantly reduced the proportions of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), thereby improving immune system effectiveness.

Single-Cell RNA Sequencing and Clinical Implications

Using single-cell RNA sequencing (scRNA-seq), this study showed that IRE1α inhibition caused significant changes in the tumor microenvironment. Reducing TAMs and regulatory T cells, in particular, helped dismantle its suppressive environment. Inhibiting IRE1α also shifted macrophages in the tumor microenvironment to a pro-inflammatory phenotype (M1 type), creating an environment that supports the immune response.

Key Findings:

• IFN-γ Signaling Pathway: Activation of the IFN-γ signaling pathway increased antigen presentation by immune cells, enhancing their ability to fight the tumor effectively.
• Reprogramming Macrophage Subtypes: The combination shifted TAMs toward a pro-inflammatory profile and reduced the number of M2-type macrophages that support tumor growth.

Future Treatment Potential and Clinical Implications

This study shows that targeting IRE1α in prostate cancer may improve the immune system's effectiveness against the tumor by reprogramming the tumor microenvironment. It is clear that IRE1α inhibition, when combined with immunotherapies, could offer a promising new treatment strategy against prostate cancer. The transition of inhibitors such as MKC8866 into clinical practice holds considerable potential, particularly for cancers resistant to immunotherapy, such as prostate cancer.

This comprehensive study provides strong findings that encourage investigation of the combination of IRE1α inhibition and immunotherapies in other solid tumor types beyond prostate cancer.

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Prof.  Fahri Saatçioğlu began studying at Ege University Faculty of Medicine in 1981. He completed half of his university education in the United States. Saatçioğlu, whose cancer discoveries frequently appear in the Turkish press, is also a Turkish scientist known for his studies on the health benefits of yoga.