2. Academic Validation
  3. Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer

Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer

  • Signal Transduct Target Ther. 2025 Dec 25;10(1):419. doi: 10.1038/s41392-025-02515-1.
Nadine Bley 1,  Alexander Rausch 2,  Simon Müller 2 3 4,  Theresa Simon 2,  Markus Glaß 2,  Danny Misiak 2,  Laura Schian 2,  Lara Meret Peters 2,  Mohammad Dipto 2,  Ali Hmedat 2 5,  Bianca Busch 2,  Annekatrin Schott 2,  Marcell Lederer 2,  Alice Wedler 2,  Robin Benedikt Rolnik 2,  Hend Elrewany 2,  Ehab Ghazy 6,  Wolfgang Sippl 6,  Martina Vetter 7,  Markus Wallwiener 7,  Stefan Hüttelmaier 8
Affiliations

Affiliations

  • 1 Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany. [email protected].
  • 2 Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • 3 New York Genome Center, New York, NY, USA.
  • 4 Department of Biology, New York University, New York, NY, USA.
  • 5 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan.
  • 6 Department of Medicinal Chemistry, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • 7 Department of Gynecology, University Hospital, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • 8 Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany. [email protected].
PMID: 41444249 DOI: 10.1038/s41392-025-02515-1
Abstract

High-grade serous ovarian Cancer (HGSC) accounts for more than 70% of ovarian cancer-related deaths, yet therapeutic progress remains stagnant. Among the four molecular subtypes reported for HGSC, the C5 subtype is distinguished by high proliferation and immune evasion with an unfavorable MHC-I/PD-L1 ratio. However, the molecular drivers of this immune desert state remain largely undefined. Here, we identify RNA-binding proteins (RBPs) as key regulators of immune evasion in C5-HGSC through integrated single-cell and bulk RNA Sequencing. We perform a targeted loss-of-function screen in C5-like cell models and find IGF2BP1 as a central mediator of immune evasion in vitro and in vivo. Mechanistically, IGF2BP1 abrogates interferon-gamma signaling by accelerating IRF1 protein degradation, thereby suppressing MHC-I presentation. We also discover that IGF2BP1 decouples PD-L1 expression from IRF1-dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation. Therapeutically, the small-molecule BTYNB effectively inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo. Multi-spectral imaging confirms these findings in human HGSC tissues and highlights the role of oncofetal RBPs as molecular drivers of the C5-HGSC subtype. This subtype-wide survey uncovers a previously unrecognized RBP-interferon regulatory axis and establishes RBP inhibition as a therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.

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