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Mevalonate kinase inhibits anti-tumor immunity by impairing the tumor cell-intrinsic interferon response in microsatellite instability colorectal cancer

Oncogene volume 44, pages 944–957 (2025)Cite this article

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Abstract

Insufficient tumor cell-intrinsic interferon response represents a major obstacle in immune checkpoint blockade (ICB) therapy, particularly in anti-PD-1 treatment. Although cholesterol metabolism has been demonstrated to be a critical regulator of anti-tumor immune responses, whether cholesterol influences tumor cell-intrinsic interferon response in microsatellite instability (MSI) colorectal cancer (CRC) remains unknown. Through comprehensive siRNA library screening and Gene Set Enrichment Analysis (GSEA), we identified mevalonate kinase (MVK) as a crucial negative regulator of tumor cell-intrinsic interferon response in MSI CRC cells. Genetic ablation of MVK resulted in significant upregulation of Th1 type chemokines (CXCL9 and CXCL10) and enhanced CD8+T cell infiltration in MSI CRC, consequently leading to marked tumor growth suppression in immunocompetent mice. At the molecular level, we demonstrated that MVK physically interacts with the transcriptional activation domain (TAD) of signal transducer and activator of transcription 1 (STAT1). This interaction substantially impairs STAT1 nuclear translocation, thereby attenuating interferon signaling cascade. Furthermore, analyses of humanized PBMC-PDX models and clinical cohorts of MSI CRC patients revealed that reduced MVK expression in tumor tissues strongly correlates with favorable responses to anti-PD-1 therapy. Collectively, our findings establish MVK as a pivotal mediator in cholesterol synthesis pathway that negatively regulates tumor cell-intrinsic interferon response in MSI CRC. These results suggest that therapeutic targeting of MVK represents a promising strategy to enhance ICB efficacy through potentiation of interferon responses in MSI CRC patients.

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Fig. 1: MVK impairs the tumor cell-intrinsic interferon response in MSI CRC.
Fig. 2: MVK influences the growth of MSI CRC via the tumor cell-intrinsic interferon response.
Fig. 3: MVK significantly modifies the cytotoxic T lymphocytes (CTL) in MSI CRC tumor.
Fig. 4: MVK impairs the phosphorylation of STAT1 within the interferon response.
Fig. 5: MVK replenishment in MVK-deficient tumor cells re-suppresses the interferon response.
Fig. 6: Suppression of MVK improves the effectiveness of immunotherapy in MSI CRC.
Fig. 7: The expression of MVK influences the immunotherapy response in MSI CRC patients.

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Data availability

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We express our heartfelt gratitude to Professor Shuijie Li of Harbin Medical University for his guidance and invaluable advice on this work. Funding for this work was provided by grants from the National Natural Science Foundation of China (nos. U22A20330, 82173233, 82373372, and 82102858), the Key Project of Research and Development Plan in Heilongjiang Province (no. 2022ZX06C01, JD2023SJ40), the Natural Science Funding of Heilongjiang (no. YQ2022H017) and Haiyan Research Fund of Harbin Medical University Cancer Hospital (JJJQ2024-02).

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  1. These authors contributed equally: Yuanyu Liao, Rui Yang, Bojun Wang.

Authors and Affiliations

  1. Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China

    Yuanyu Liao, Rui Yang, Bojun Wang, Yuli Ruan, Luying Cui, Jiani Yang, Xuefan Yu, Shuling Han, Yuanfei Yao, Xindi Luan, Yingjue Li, Mengde Shi, Chao Liu & Yanqiao Zhang

  2. Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China

    Yuanyu Liao, Rui Yang, Bojun Wang, Yuli Ruan, Luying Cui, Jiani Yang, Xuefan Yu, Shuling Han, Yuanfei Yao, Xindi Luan, Yingjue Li, Mengde Shi, Chao Liu & Yanqiao Zhang

  3. Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China

    Yuanyu Liao, Rui Yang, Bojun Wang, Yuli Ruan, Luying Cui, Jiani Yang, Xuefan Yu, Shuling Han, Yuanfei Yao, Xindi Luan, Yingjue Li, Mengde Shi, Chao Liu & Yanqiao Zhang

  4. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, China

    Shuijie Li

  5. Heilongjiang Province Key Laboratory of Research on Molecular Targeted Anti-Tumor Drugs, Harbin, China

    Shuijie Li

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Contributions

YYL, CL, and YQZ designed the study. YYL, RY, and BJW performed the experiments, and performed data analysis. YLR, LYC, JNY, XFY, YFY, MDS, XDL, and SLH performed the experiments and performed data analysis. YYL and YJL wrote the manuscript. SJL,CL and YQZ supervised the study and acquired the funding. All authors edited and revised the manuscript and were involved in the final approval of the manuscript.

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Correspondence to Shuijie Li, Chao Liu or Yanqiao Zhang.

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Liao, Y., Yang, R., Wang, B. et al. Mevalonate kinase inhibits anti-tumor immunity by impairing the tumor cell-intrinsic interferon response in microsatellite instability colorectal cancer. Oncogene 44, 944–957 (2025). https://doi.org/10.1038/s41388-024-03255-2

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