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<p>Glioblastoma (GBM), the most aggressive central nervous system (CNS) malignancy, currently lacks curative therapeutic options. While immunotherapy has revolutionized treatment for many cancers, GBM remains refractory to immune-based interventions due to the absence of effective immunotherapeutic targets. Here, through CRISPR screening, we identify Niemann–Pick C1-like 1 (NPC1L1) as a previously unrecognized key driver of GBM progression. Mechanistically, NPC1L1 modulates cholesterol metabolism to concurrently enhance tumor cell stemness and suppress CD8<sup>+</sup> T-cell activation, thus inducing tumor progression. Notably, combined treatment with ezetimibe (NPC1L1 inhibitor) and anti-PD-1 antibody elicited potent antitumor activity in GBM orthotopic mouse models. Collectively, these findings establish NPC1L1 as a critical regulator of GBM pathogenesis, underscoring the translational potential of targeting NPC1L1-mediated cholesterol metabolism for developing novel GBM immunotherapies.</p>

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CRISPR screening reveals NPC1L1 as a key driver of glioblastoma progression via cholesterol metabolic regulation

  • 期刊论文

  • 发表日期：

    2026年7月17日

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  • Xiao Liu,
  • Guangzhao Yang,
  • Haozhe Qin,
  • Qi Zhang,
  • Zhihao Guan,
  • Maorong Zhu,
  • Cheng Zou,
  • Yawen Wang,
  • Yuxin Wu,
  • Duo Yu,
  • Dan Zheng,
  • Juan Li,
  • Jintao Gu,
  • Zhengcong Cao,
  • Zhengmin Li,
  • Yalong He,
  • Wei Lin

摘要

Glioblastoma (GBM), the most aggressive central nervous system (CNS) malignancy, currently lacks curative therapeutic options. While immunotherapy has revolutionized treatment for many cancers, GBM remains refractory to immune-based interventions due to the absence of effective immunotherapeutic targets. Here, through CRISPR screening, we identify Niemann–Pick C1-like 1 (NPC1L1) as a previously unrecognized key driver of GBM progression. Mechanistically, NPC1L1 modulates cholesterol metabolism to concurrently enhance tumor cell stemness and suppress CD8+ T-cell activation, thus inducing tumor progression. Notably, combined treatment with ezetimibe (NPC1L1 inhibitor) and anti-PD-1 antibody elicited potent antitumor activity in GBM orthotopic mouse models. Collectively, these findings establish NPC1L1 as a critical regulator of GBM pathogenesis, underscoring the translational potential of targeting NPC1L1-mediated cholesterol metabolism for developing novel GBM immunotherapies.