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
  • 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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