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One particularly aggressive form of ovarian cancer responds poorly to conventional therapies and can effectively evade the immune system. Researchers at University Medicine Halle have uncovered the mechanisms behind this immune evasion and successfully blocked them in cell cultures and animal models. Experiments showed that this approach was capable overcoming immune evasion and improving therapeutic efficacy. The research, presented in the Nature portfolio journal “Signal Transduction and Targeted Therapy”, opens up new strategies for treating ovarian cancer. The team is currently developing and patenting new drug candidates that are expected to be even more stable and effective.
More than two-thirds of deaths from ovarian cancer are attributable to high-grade serous carcinoma. In one particularly aggressive form, only a small number of inactive immune cells can be found near the tumor. Such tumors are referred to as immunologically cold. “Immune checkpoint therapy is one way to sharpen the body’s own defenses. The therapy releases the brakes on the immune system so that it starts reacting to the tumor again. However, this form of therapy is largely ineffective for this type of cancer,” explains Professor Stefan Hüttelmaier, Director of the Institute for Molecular Medicine at University Medicine Halle, who also headed the study.
By analyzing hundreds of patient tumors and pioneering single-cell analysis on fresh surgical samples from local patients at University Medicine Halle, the researchers identified a protein called IGF2BP1 as the tumor's cloaking device.
“Normally, our immune system recognizes tumor cells by certain molecules on their cell surface—a kind of biological fingerprint that signals that something is wrong. However, IGF2BP1 alters this marker so significantly that the immune system becomes blind to these tumor cells,” explains Dr. Nadine Bley, research associate and first author of the study. The results therefore suggest that the persistent camouflaging of cancer cells is what is limiting how well immune checkpoint therapies work.
Next, the researchers investigated the therapeutic effects of blocking IGF2BP1 specifically, both on its own and in combination with immune checkpoint therapy. For comparison, they assessed the impact of immune checkpoint therapy alone and no treatment. All experiments were conducted in cell cultures and mouse models.
The combined use of the investigated drug candidate and immune checkpoint therapy led to a significant increase in immune cells and a simultaneous decrease in tumor cells. The tumor also became more susceptible to the immune cells.
“We essentially turned 'cold' tumors into 'hot' ones that respond to treatment. For the first time, we were able to demonstrate that IGF2BP1 plays a key role in this aggressive form of ovarian cancer, and that blocking it again makes the tumor vulnerable. IGF2BP1 is an RNA-binding protein that is usually only active during embryonic development. As it is rarely found in adults, this offers a promising new treatment approach. This is the first demonstration that targeting an RNA-binding protein can overcome innate immune resistance in ovarian cancer,” emphasizes Hüttelmaier.
Before clinical trials can begin, extensive toxicity studies are needed to confirm that no relevant side effects occur.
The team worked in close cooperation with the group led by Professor Wolfgang Sippl from the Institute of Pharmacy at Martin Luther University Halle-Wittenberg. Together they succeeded in developing further experimental drug candidates, some of which have already been patented. These are expected to block the IGF2BP1 protein even more effectively. Current research is focusing on increasing the stability of the substances in the body so that they can combat the tumor as successfully as possible.
The study was conducted as part of the DFG-funded research unit “RNA in Focus” (RU 5433) and the DFG-funded research training group “InCuPANC” (RTG 2751).
University Medicine Halle
Institute for Molecular Medicine
Professor Stefan Hüttelmaier, Director
stefan.huettelmaier@medizin.uni-halle.de
Bley N, […], Hüttelmaier S. Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer. Signal Transduct Target Ther. 2025 Dec 25;10(1):419. doi: https://doi.org/10.1038/s41392-025-02515-1
Professor Stefan Hüttelmaier and Dr Nadine Bley in the laboratory at the Institute for Molecular Med ...
Copyright: University Medicine Halle
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