Letter | Accelerated Article Preview

Cyclin D–CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance

Published online:


Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit1,2. However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not well understood3–5. Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells6,7. Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients. Here, we report that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the Cullin 3SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4/6 in vivo elevates PD-L1 protein levels, largely by inhibiting cyclin D–CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by APC/CCdh1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumor regression and dramatically improves overall survival rates in mouse tumor models. Our study uncovers a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.

  • Subscribe to Nature for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Author information

Author notes

    • Jinfang Zhang
    • , Xia Bu
    •  & Haizhen Wang

    These authors contributed equally to this study.

    • Gordon J. Freeman
    • , Piotr Sicinski
    •  & Wenyi Wei

    These authors jointly supervised this work.


  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

    • Jinfang Zhang
    • , Naoe Taira Nihira
    • , Yuyong Tan
    • , Yanpeng Ci
    • , Fei Wu
    • , Xiangpeng Dai
    • , Jianping Guo
    • , Yu-Han Huang
    •  & Wenyi Wei
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

    • Xia Bu
    •  & Gordon J. Freeman
  3. Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA

    • Haizhen Wang
    • , Yan Geng
    • , Caoqi Fan
    •  & Piotr Sicinski
  4. Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China

    • Yasheng Zhu
    • , Shancheng Ren
    •  & Yinghao Sun
  5. Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha 410011, P.R. China

    • Yuyong Tan
  6. School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, P.R. China

    • Yanpeng Ci
  7. Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China

    • Fei Wu
  8. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Peking University, Beijing 100871, P.R. China

    • Caoqi Fan


  1. Search for Jinfang Zhang in:

  2. Search for Xia Bu in:

  3. Search for Haizhen Wang in:

  4. Search for Yasheng Zhu in:

  5. Search for Yan Geng in:

  6. Search for Naoe Taira Nihira in:

  7. Search for Yuyong Tan in:

  8. Search for Yanpeng Ci in:

  9. Search for Fei Wu in:

  10. Search for Xiangpeng Dai in:

  11. Search for Jianping Guo in:

  12. Search for Yu-Han Huang in:

  13. Search for Caoqi Fan in:

  14. Search for Shancheng Ren in:

  15. Search for Yinghao Sun in:

  16. Search for Gordon J. Freeman in:

  17. Search for Piotr Sicinski in:

  18. Search for Wenyi Wei in:

Corresponding authors

Correspondence to Gordon J. Freeman or Piotr Sicinski or Wenyi Wei.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    This file contains the source data for gels in Figures 1–4 and Extended Data Figures 1–9.

  2. 2.

    Life Sciences Reporting Summary

  3. 3.

    Gating strategy


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.