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<p>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/<i>PD-L1</i> 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 <i>IGF2BP1</i> as a central mediator of immune evasion in vitro and in vivo. Mechanistically, <i>IGF2BP1</i> abrogates interferon-gamma signaling by accelerating <i>IRF1</i> protein degradation, thereby suppressing MHC-I presentation. We also discover that <i>IGF2BP1</i> decouples <i>PD-L1</i> expression from <i>IRF1</i>-dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation. Therapeutically, the small-molecule BTYNB effectively inhibits <i>IGF2BP1</i> 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.</p>

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Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月25日

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  • Nadine Bley,
  • Alexander Rausch,
  • Simon Müller,
  • Theresa Simon,
  • Markus Glaß,
  • Danny Misiak,
  • Laura Schian,
  • Lara Meret Peters,
  • Mohammad Dipto,
  • Ali Hmedat,
  • Bianca Busch,
  • Annekatrin Schott,
  • Marcell Lederer,
  • Alice Wedler,
  • Robin Benedikt Rolnik,
  • Hend Elrewany,
  • Ehab Ghazy,
  • Wolfgang Sippl,
  • Martina Vetter,
  • Markus Wallwiener,
  • Stefan Hüttelmaier

摘要

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.