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

Cell Death & Differentiation (2026)Cite this article

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Abstract

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.

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Fig. 1: Upregulation of WIP1 in CRC.
Fig. 2: WIP1 promoted CRC via remodeling tumor microenvironment.
Fig. 3: WIP1 inhibition augmented type I IFN signaling to engage macrophages.
Fig. 4: WIP1 inhibition increased cytoplasmic dsDNA to activate cGAS-STING-TBK1 signaling.
Fig. 5: WIP1 directly dephosphorylated TBK1 to inactivate type I IFN signaling for immunosuppression.
Fig. 6: WIP1 inhibition enhanced the anti-cancer efficacy of STING agonist.
Fig. 7: Combination of WIP1 inhibitor and STING agonist sensitized anti-PD-1 immunotherapy.
Fig. 8: Working model.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82203071 to J X), Zhejiang Provincial Natural Science Foundation (LY23H160018 to J S), the Huadong Medicine Joint Fund of the Zhejiang Provincial Natural Science Foundation of China (HDMY26H160069 to P Y), the Medical Science and Technology Project of Zhejiang Province (2024KY1143 to DC).

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  1. These authors contributed equally: Lini Chen, Miaoqin Chen.

Authors and Affiliations

  1. Department of Medical Oncology, Zhejiang Key Laboratory of Multi-omics Precision Diagnosis and Treatment of Liver Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

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

  2. Department of Radiation Oncology Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jinye Xu

  3. Department of General Surgery, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China

    Dingwei Chen

  4. Department of Pathology, People’s Hospital of Dongyang, Jinhua, China

    Chaoqun Wang

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Contributions

HJ, LF, and XW designed the study; HJ and LF analyzed the data and wrote the manuscript; LC, MC, SY, YW, HW, LZ, CSW, JX, JS, DC, PY, CW, and CL performed the experiments. All authors read and approved the final manuscript.

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Correspondence to Xian Wang, Lifeng Feng or Hongchuan Jin.

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The authors declare no competing interests.

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The mice xenograft study was approved by the animal ethics committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. Animal care and experiments were conducted in compliance with Institutional Animal Care and Use Committee and NIH guidelines.

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Chen, L., Chen, M., Yuan, S. et al. Targeting WIP1 reprograms immunosuppressive tumor microenvironment to potentiate immunotherapy response in colorectal cancer. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01710-z

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