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<p>While immunotherapy based on immune checkpoint inhibitors (ICIs) shows limited efficacy in colorectal cancer (CRC) due to its immunosuppressive&#xa0;tumor microenvironment, strategies to activate innate immunity remain underexplored. Here, we identified wild-type p53-induced phosphatase 1 (WIP1/<i>PPM1D</i>) as a critical immunosuppressive driver in CRC, with its expression significantly upregulated in tumor tissues. Genetic or pharmacological inhibition of WIP1 robustly suppressed tumor growth by remodeling the tumor immune microenvironment, marked by increased infiltration of anti-tumor macrophages and cytotoxic&#xa0;T cells. Mechanistically, WIP1 inhibited type I interferon (IFN) signaling by reducing cytoplasmic dsDNA accumulation to inactivate the cGAS-STING-TBK1 axis, and&#xa0;by directly dephosphorylating TBK1 at Ser172 to suppress its kinase activity. Strikingly, combining a WIP1 inhibitor with a STING agonist synergistically enhanced anti-tumor efficacy by amplifying IFNβ production to activate anti-tumor immune response. This combination further potentiated anti-PD-1 immunotherapy. In summary, this study uncovers WIP1 as a pioneering dual-functional suppressor of tumor-intrinsic STING activation and establishes a rationally designed “STING-WIP1 co-targeting” strategy to reverse immunotherapy resistance. Our findings bridge genomic instability with adaptive immune evasion, offering a roadmap for precision immunotherapy in CRC.</p>

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Targeting WIP1 reprograms immunosuppressive tumor microenvironment to potentiate immunotherapy response in colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年3月19日

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  • Lini Chen,
  • Miaoqin Chen,
  • Shijin Yuan,
  • Yanmei Wang,
  • Hanying Wang,
  • Liyuan Zhu,
  • Chandra Sugiarto Wijaya,
  • Jinye Xu,
  • Jiaying Shen,
  • Dingwei Chen,
  • Pingting Ying,
  • Chaoqun Wang,
  • Chentao Li,
  • Xian Wang,
  • Lifeng Feng,
  • Hongchuan Jin

摘要

While immunotherapy based on immune checkpoint inhibitors (ICIs) shows limited efficacy in colorectal cancer (CRC) due to its immunosuppressive tumor microenvironment, strategies to activate innate immunity remain underexplored. Here, we identified wild-type p53-induced phosphatase 1 (WIP1/PPM1D) as a critical immunosuppressive driver in CRC, with its expression significantly upregulated in tumor tissues. Genetic or pharmacological inhibition of WIP1 robustly suppressed tumor growth by remodeling the tumor immune microenvironment, marked by increased infiltration of anti-tumor macrophages and cytotoxic T cells. Mechanistically, WIP1 inhibited type I interferon (IFN) signaling by reducing cytoplasmic dsDNA accumulation to inactivate the cGAS-STING-TBK1 axis, and by directly dephosphorylating TBK1 at Ser172 to suppress its kinase activity. Strikingly, combining a WIP1 inhibitor with a STING agonist synergistically enhanced anti-tumor efficacy by amplifying IFNβ production to activate anti-tumor immune response. This combination further potentiated anti-PD-1 immunotherapy. In summary, this study uncovers WIP1 as a pioneering dual-functional suppressor of tumor-intrinsic STING activation and establishes a rationally designed “STING-WIP1 co-targeting” strategy to reverse immunotherapy resistance. Our findings bridge genomic instability with adaptive immune evasion, offering a roadmap for precision immunotherapy in CRC.