SKP2 at the crossroads of proliferation and immune evasion: a new target in the tumor microenvironment

Author contributions

Panagiotis J. Vlachostergios (Writing—original draft, Data curation, Writing—review & editing), and Stergios Boussios (Writing—review & editing, Resources, Supervision).

Conflict of interest

None declared.

Notes

Editor’s note: A commentary on “A pan-cancer analysis revealed as an inhibitor of the tumor immune microenvironment and a promising therapeutic target for immunotherapy”

References

[1] Anderson NM, Simon MC. The tumor microenvironment. Curr Biol 2020;30:R921-5. https://doi.org/10.1016/j.cub.2020.06.081

[2] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74. https://doi.org/10.1016/j.cell.2011.02.013

[3] Vlachostergios PJ, Karathanasis A, Dimitropoulos K et al. High PSMA expression is associated with immunosuppressive tumor microenvironment in clear cell renal cell carcinoma. Precis Clin Med 2024;7:pbae010. https://doi.org/10.1093/pcmedi/pbae010

[4] Wu T, Gu X, Cui H. Emerging roles of SKP2 in cancer drug resistance. Cells 2021;10:1147. https://doi.org/10.3390/cells10051147

[5] Liao X, Zhang Y, Yu X et al. A pan-cancer analysis revealed SKP 2 as an inhibitor of the tumor immune microenvironment and a promising therapeutic target for immunotherapy. Precis Clin Med 2025;8:pbaf022. https://doi.org/10.1093/pcmedi/pbaf022

[6] Hu K, Zhao L, Miao P et al. Inhibition of Skp2 enhances antitumor immunity of macrophages by regulating CD47 in gastric cancer. Int Immunopharmacol 2025;163:115262. https://doi.org/10.1016/j.intimp.2025.115262

[7] Peng Y, Qi X, Ding L et al. SKP 2 inhibition activates tumor cellintrinsic immunity by inducing DNA replication stress and genomic instability. BrJ Cancer 2025;132:81-92. https://doi.org/10.1038/s41416-024-02909-y

[8] Lv L, Miao Q, Zhan S et al. LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PDL1 protein in non-small cell lung cancer. J Immunother Cancer 2024;12:e009444. https://doi.org/10.1136/jitc-2024-009444

[9] Ferrena A, Wang J, Zhang R et al. SKP 2 Knockout in Rb1/p53deficient mouse models of osteosarcoma induces immune infiltration and drives a transcriptional program with a favorable prognosis. Mol Cancer Ther 2024;23:223-34. https://doi.org/10.1158/1535-7163.MCT-23-0173

[10] Wu Y, Li J, Yang X et al. Immunosensitivity mediated by downregulated AKT1-SKP 2 induces anti-PD-1-associated thyroid immune injury. Int Immunopharmacol 2023;121:110452. https://doi.org/10.1016/j.intimp.2023.110452

[11] Kamel EM, Khadrawy SM, Allam AA et al. Targeting the Skp2Cks 1 protein-protein interaction: structures, assays, and preclinical inhibitors. Eur J Pharmacol 2025;1006:178129. https://doi.org/10.1016/j.ejphar.2025.178129

[12] Yu P, Li J, Feng W et al. SKP 2 ubiquitylation modifies IDH1 to regulate hepatoblastoma cell cycle and glucose metabolism. BMC Cancer 2025;25:1304. https://doi.org/10.1186/s12885-025-14644-5

[13] Chu Y, Chen S, Yang M et al. A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2. Nat Biotechnol 2025. https://doi.org/10.1038/s41587-025-02793-8