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<p>The efficacy of immune checkpoint inhibitors (ICIs) in microsatellite stable colorectal cancer (MSS CRC) remains limited, highlighting an urgent need for predictive biomarkers. Through multi-omics analysis, we identified two novel MSS CRC subtypes, termed DUB-H and DUB-L. The DUB-L subtype exhibited an inflamed tumor immune microenvironment, a superior response to immune therapy, and better recurrence-free survival (RFS) compared to DUB-H. The classifier gene USP7 was selected as a gene of interest due to its specific expression profile, which is highly expressed in MSS CRC but not in microsatellite instability-high (MSI-H) tumors, and strongly correlated with suppressed immune infiltration. Large-scale clinical analyses confirmed associations between high USP7 expression, microsatellite stability, specific consensus molecular subtypes (CMS), and unfavorable prognosis. Single-cell analysis and multiplex immunofluorescence validated an immune-desert phenotype in USP7-high MSS tumors. Mechanistically, USP7 knockdown in MSS CRC cells enhances the secretion of T-cell-recruiting chemokines (CXCL9/10/11), promoting CD8⁺ T cell recruitment and cytotoxicity in vitro. In vivo experiments demonstrated that USP7 blockade enhanced the efficacy of anti-PD-1 treatment in MSS CRC models by remodeling the tumor immune microenvironment, increasing infiltration and function of CD8⁺ T and NK cells. Consistently, low USP7 expression is associated with a better response to anti-PD-1 therapy. Overall, we propose a novel DUB-based classification system for MSS CRC and demonstrate that targeting USP7 may overcome immunotherapy resistance by converting immunologically “cold” tumors into “hot” ones.</p>

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Immune-related deubiquitylation spectrum of microsatellite stability colorectal cancer reveals USP7 as a potential immunotherapeutic target

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Xiaomao Yin,
  • Jinran Wu,
  • Mi-die Xu,
  • Tongguan Tian,
  • Lin Zhu,
  • Jiexuan Wang,
  • Xuan Dai,
  • Xin Yang,
  • Jingjing Qian,
  • Wenqiang Wang,
  • Liangchen Zhu,
  • Zekun Zhao,
  • Kai Xu,
  • Yanping Xu,
  • Xinxing Li,
  • Zhiqian Hu

摘要

The efficacy of immune checkpoint inhibitors (ICIs) in microsatellite stable colorectal cancer (MSS CRC) remains limited, highlighting an urgent need for predictive biomarkers. Through multi-omics analysis, we identified two novel MSS CRC subtypes, termed DUB-H and DUB-L. The DUB-L subtype exhibited an inflamed tumor immune microenvironment, a superior response to immune therapy, and better recurrence-free survival (RFS) compared to DUB-H. The classifier gene USP7 was selected as a gene of interest due to its specific expression profile, which is highly expressed in MSS CRC but not in microsatellite instability-high (MSI-H) tumors, and strongly correlated with suppressed immune infiltration. Large-scale clinical analyses confirmed associations between high USP7 expression, microsatellite stability, specific consensus molecular subtypes (CMS), and unfavorable prognosis. Single-cell analysis and multiplex immunofluorescence validated an immune-desert phenotype in USP7-high MSS tumors. Mechanistically, USP7 knockdown in MSS CRC cells enhances the secretion of T-cell-recruiting chemokines (CXCL9/10/11), promoting CD8⁺ T cell recruitment and cytotoxicity in vitro. In vivo experiments demonstrated that USP7 blockade enhanced the efficacy of anti-PD-1 treatment in MSS CRC models by remodeling the tumor immune microenvironment, increasing infiltration and function of CD8⁺ T and NK cells. Consistently, low USP7 expression is associated with a better response to anti-PD-1 therapy. Overall, we propose a novel DUB-based classification system for MSS CRC and demonstrate that targeting USP7 may overcome immunotherapy resistance by converting immunologically “cold” tumors into “hot” ones.