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Cellular and Molecular Biology

SKP2 inhibition activates tumor cell-intrinsic immunity by inducing DNA replication stress and genomic instability

British Journal of Cancer volume 132, pages 81–92 (2025)Cite this article

Subjects

Abstract

Background

S-phase kinase-associated protein 2 (SKP2) is a typical oncogene aberrantly overexpressing in a variety of cancer types, but it remains elusive whether SKP2 regulates the antitumor immunity of triple-negative breast cancer.

Methods

The efficacy of anti-PD-1 was evaluated in the orthotopic xenografts of immunocompetent mice models. The infiltration of cytotoxic T cells in tumor microenvironment(TME) were assessed by immunofluorescence staining. The levels of pro-inflammatory chemokines were analyzed by ELISA. The protein interaction was analyzed by co-immunoprecipitation and GST pull-down. The genomic instability was analyzed by fluorescent microscopy.

Results

SKP2 inhibition significantly improved the antitumor efficacy of immune checkpoint blockade (ICB). Furthermore, SKP2 inhibition activated the cGAS/STING signal pathway and induced the secretion of pro-inflammatory chemokines, thereby promoting cytotoxic T cell infiltration. Additionally, we identified CDC6, a DNA replication licensing factor as a novel substrate of SKP2 in addition to CDT1. SKP2 induced protein degradation of CDC6 and CDT1 through the ubiquitin-proteasome pathway. Conversely, SKP2 inhibition elevated CDC6 and CDT1 protein levels, which caused DNA aberrant replication, DNA damage and genomic instability, thereby resulting in the accumulation of cytosolic DNA, activating cGAS/STING signaling pathway and improving antitumor immunity.

Conclusion

SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy.

Social media

Peng et al. found that SKP2 inhibition improved the antitumor immunotherapy by activating tumor cell-intrinsic immunity, thereby providing evidences that SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy.

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Fig. 1: SKP2 depletion inhibited tumor growth and enhanced T cell infiltration.
Fig. 2: SKP2 Inhibition activated the cGAS/STING signaling pathway and induced the secretion of pro-inflammatory cytokines/chemokines.
Fig. 3: SKP2 knockdown induced aberrant DNA replication and caused DNA damage and genomic instability.
Fig. 4: SKP2 regulates CDC6 protein ubiquitylation and degradation.
Fig. 5: SKP2 knockdown activated cGAS/STING signaling pathway through the aberrant elevation of CDC6 and CDT1.
Fig. 6: SKP2 inhibition enhanced tumor sensitivity to anti-PD-1 immunotherapy.

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Data availability

The raw data of RNA sequencing are deposited in the NCBI’s Bioproject database (BioProject ID: PRJNA1058858).

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Acknowledgements

We appreciate Personal Biotechnology Co., Ltd (Shanghai, China) for RNAseq analysis.

Funding

This work was supported by grants from the National Natural Science Foundation of China (NSFC 81874096、NSFC 82303867 and NSFC 81572542), Research Project of Key Discipline of Guangdong Province (2019GDXK0010), Science and Technology Program of Guangzhou City (202201010161), Key team of basic and clinical research on tumor immunotherapy, Guangdong Pharmaceutical University, Project No. 2024ZZ10 and the 2024 Science and Technology Innovation Project of Guangdong Medical Products Administration “Research and Evaluation of Key Technologies for Drug Safety Risk Management” (No. 2024ZDZ10).

Author information

Author notes

  1. These authors contributed equally: Yuchong Peng, Xuli Qi.

Authors and Affiliations

  1. Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China

    Yuchong Peng, Liuyang Ding, Jingjing Huang, Rirong Zheng, Yongming Fu, Tanggang Deng, Yubing Ye & Xiong Li

  2. Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China

    Yuchong Peng, Liuyang Ding, Jingjing Huang, Rirong Zheng, Yongming Fu, Tanggang Deng, Yubing Ye & Xiong Li

  3. NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China

    Yuchong Peng, Liuyang Ding, Jingjing Huang, Rirong Zheng, Yongming Fu, Tanggang Deng, Yubing Ye & Xiong Li

  4. Institute of Integrative Neurology of integrated traditional Chinese and Western Medicine, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China

    Yuchong Peng & Yongming Fu

  5. School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China

    Xuli Qi & Xiong Li

  6. Department of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Youhong Liu

  7. Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Youhong Liu

  8. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China

    Linglong Yin

  9. Department of Tumor Immunity, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China

    Size Chen

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Contributions

YCP performed experiments, analyzed data and wrote the manuscript; XLQ performed experiments and wrote the manuscript; LYD, YHL and SZC participated in data analysis; JJH participated in animal studies and ELISA assays; RRZ participated in the real-time quantitative PCR; YMF participated in co-IP assays; LLY, TGD and YBY participated in Western Blot and ubiquitination assays; LX designed the project, supervised all experiments, analyzed the results, and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiong Li.

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The authors declare no competing interests.

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All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at the Institute of Laboratory Animal Science (License Number:00320412), Guangdong Pharmaceutical University (Guangzhou, China), and conformed to the relevant regulatory standards.

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Peng, Y., Qi, X., Ding, L. et al. SKP2 inhibition activates tumor cell-intrinsic immunity by inducing DNA replication stress and genomic instability. Br J Cancer 132, 81–92 (2025). https://doi.org/10.1038/s41416-024-02909-y

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