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<p>The mechanisms underlying the limited response to immune checkpoint blockade (ICB) remain unclear. One explanation is that tumors escape cytotoxic T cell killing by disrupting interferon-gamma (IFN-γ) signaling. Here we show that guanylate-binding protein 2 (GBP2), an IFN-γ–inducible molecule, functions as a general amplifier of T cell–mediated cytotoxicity by promoting ferroptosis in melanoma. GBP2 enhances STAT1 activation and suppresses SLC7A11, thereby sensitizing tumor cells to ferroptotic death. Upon IFN-γ stimulation, GBP2 undergoes phase separation through an intrinsically disordered region, forming condensates that sequester SHP1 and sustain STAT1 activation. Disrupting GBP2 phase separation impairs ferroptosis, accelerates tumor growth, and weakens T cell–driven tumor control. GBP2 also increases HMGB1 release from ferroptotic cells, promoting cytotoxic T cell infiltration. These findings identify GBP2 as a key mediator linking IFN-γ signaling to ferroptosis and demonstrate that enhancing this pathway can improve tumor responsiveness to ICB immunotherapy.</p>

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GBP2 condensates promote ferroptosis to sensitize anti-PD-L1 immunotherapy in melanoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月24日

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  • Xin Liu,
  • Shilin Fang,
  • Xianghai Ren,
  • Yuntian Hong,
  • Jianchun Guo,
  • Xiaoping Liu,
  • Liping Gao,
  • Haihang Nie,
  • Yumei Ning,
  • Meng Zhang,
  • Fei Xu,
  • Lan Liu,
  • Jun Fang,
  • Yu Pang,
  • Qiu Zhao,
  • Fan Wang,
  • Haizhou Wang

摘要

The mechanisms underlying the limited response to immune checkpoint blockade (ICB) remain unclear. One explanation is that tumors escape cytotoxic T cell killing by disrupting interferon-gamma (IFN-γ) signaling. Here we show that guanylate-binding protein 2 (GBP2), an IFN-γ–inducible molecule, functions as a general amplifier of T cell–mediated cytotoxicity by promoting ferroptosis in melanoma. GBP2 enhances STAT1 activation and suppresses SLC7A11, thereby sensitizing tumor cells to ferroptotic death. Upon IFN-γ stimulation, GBP2 undergoes phase separation through an intrinsically disordered region, forming condensates that sequester SHP1 and sustain STAT1 activation. Disrupting GBP2 phase separation impairs ferroptosis, accelerates tumor growth, and weakens T cell–driven tumor control. GBP2 also increases HMGB1 release from ferroptotic cells, promoting cytotoxic T cell infiltration. These findings identify GBP2 as a key mediator linking IFN-γ signaling to ferroptosis and demonstrate that enhancing this pathway can improve tumor responsiveness to ICB immunotherapy.