A pan-cancer analysis revealed SKP2 as an inhibitor of the tumor immune microenvironment and a promising therapeutic target for immunotherapy

Abstract

Background: S-Phase kinase associated protein 2 (SKP2) is a key regulator of the cell cycle and proliferation linked to cancer development. Our recent study has revealed that knocking out Skp2 in a mouse model significantly activates anti-tumor immunity. Although several studies have examined SKP2 in relation to the tumor immune microenvironment using public datasets, a comprehensive pan-cancer evaluation that integrates multi-omics layers and in vivo validation has remained limited.

Methods: In this study, we integrated multi-omics data from diverse public datasets to comprehensively analyze SKP2 expression characteristics and its relationship to tumor immunity across pan-cancer. A multiplex immunofluorescence assay was performed on tumors from Skp2 knockout and Skp2-intact mouse models for validation.

Results: Our findings indicate that SKP2 is overexpressed in various cancer types, leading to poor prognosis. Single-cell transcriptomic analyses further revealed that SKP2 is predominantly expressed in malignant and immune cells. Notably, a multiplex immunofluorescence assay on tumors from Skp2 knockout and Skp2-intact mouse models and pan-cancer data unveiled a correlation between SKP2 and the “immune-cold” microenvironment, which, possibly linked to the weakened antigen presentation, reduced secretion of chemokines in SKP2-overexpressing cancers. Additionally, we observed that SKP2 overexpression predicts worse immunotherapy efficacy.

Conclusion: Our findings provide novel insights into the role of SKP2 in regulating the tumor immune microenvironment, suggesting targeting SKP2 as a promising strategy to enhance immunotherapy efficacy in pan-cancer settings.

Keywords

SKP2 / tumor immune microenvironment / pan-cancer / multi-omics / prognosis

Acknowledgements

We sincerely thank the public databases for providing the comprehensive data, and all bioinformatics tools for data analysis. This study is supported by grants provided by National Natural Science Foundation of China (grant Nos. 82103223 and 82303165), Peking University People’s Hospital Scientific Research Development Funds (grant No. RDX2022-01), Peking University Clinical Scientist Training Program (grant No. BMU2023PYJH015), Beijing Physician Scientist Training Project (BJPSTP-2024-10), and National Institutes of Health (grant No. R01CA255643).

Author contributions

Xingyu Liao (Writing - original draft), Yaxin Zhang (Visualization), Xue Yu (Data curation, Resources, Software), Wei Du (Resources, Software), Linxi Chen (Resources, Software), Zhiqing Zhao (Resources, Software), Haijie Liang (Resources, Software), Xingyu Liu (Resources, Software), Feiyang Qi (Resources, Software), David S. Geller (Resources, Software), Rui Yang (Resources, Software), Bang H. Hoang (Resources, Software), Li Hu (Supervision, Writing - original draft, Writing - review & editing), and Jichuan Wang (Resources, Supervision, Writing - review & editing).

Supplementary data

Supplementary data is available at PCMEDI Journal online.

Conflict of interest

None declared.

Ethics statement

All animals were housed under pathogen-free conditions at the Beijing Key Laboratory for Musculoskeletal Tumors animal facility. The experimental procedures were reviewed and approved by the Ethics Committee of Peking University People’s Hosptial (2024PHB432-001), following established guidelines for ethical animal care. All methods are reported in accordance with Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.

Data availability

Transcriptome and genomic data of 33 cancers and corresponding normal samples were obtained from TCGA and GTEx. Protein expression data of SKP2 in various cancers were obtained from the Human Protein Atlas (HPA) database. scRNA-seq data were obtained from The Tumor Immune Single-cell Hub (TISCH) database and CancerSEA. Any additional information required is available from the corresponding author upon reasonable request.

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