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<p>Immune checkpoint blockade (ICB) remains ineffective in most colorectal cancers (CRC) due to intrinsic immune resistance. We identify guanylate-binding protein 2 (GBP2) as a key enhancer of ICB response through modulation of the gasdermin D (GSDMD)–Yes-associated protein (YAP) axis. Analyses of CRC cohorts, patient samples, organoids, and mouse models revealed that GBP2 directly binds GSDMD, inhibiting its cleavage-dependent activation and preventing YAP nuclear translocation. Activated GSDMD facilitates YAP nuclear accumulation, which represses CXCL9/10/11 transcription and limits CD8⁺ T-cell infiltration. Mechanistically, GBP2 disrupts this process by restraining non-pyroptotic GSDMD activity and maintaining YAP in its inactive cytoplasmic state. Genetic or pharmacologic inhibition of GSDMD restored YAP inactivation and sensitized tumors to anti–PD-L1 therapy. These findings define a GBP2–GSDMD–YAP signaling axis that inhibits immune evasion and represents a therapeutic target to overcome ICB resistance in CRC.</p>

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GBP2 enhances anti–PD-L1 response in colorectal cancer via GSDMD-mediated YAP nuclear translocation by non-pyroptotic

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Haihang Nie,
  • Yali Yu,
  • Jingkai Zhou,
  • Yumei Ning,
  • ChunXiao Leng,
  • Peishan Qiu,
  • Yuntian Hong,
  • Fei Xu,
  • Qiu Zhao,
  • Haizhou Wang,
  • Fan Wang

摘要

Immune checkpoint blockade (ICB) remains ineffective in most colorectal cancers (CRC) due to intrinsic immune resistance. We identify guanylate-binding protein 2 (GBP2) as a key enhancer of ICB response through modulation of the gasdermin D (GSDMD)–Yes-associated protein (YAP) axis. Analyses of CRC cohorts, patient samples, organoids, and mouse models revealed that GBP2 directly binds GSDMD, inhibiting its cleavage-dependent activation and preventing YAP nuclear translocation. Activated GSDMD facilitates YAP nuclear accumulation, which represses CXCL9/10/11 transcription and limits CD8⁺ T-cell infiltration. Mechanistically, GBP2 disrupts this process by restraining non-pyroptotic GSDMD activity and maintaining YAP in its inactive cytoplasmic state. Genetic or pharmacologic inhibition of GSDMD restored YAP inactivation and sensitized tumors to anti–PD-L1 therapy. These findings define a GBP2–GSDMD–YAP signaling axis that inhibits immune evasion and represents a therapeutic target to overcome ICB resistance in CRC.