Using in vivo CRISPR–Cas9 screens of CD8+ T cells in a melanoma model, we identified STUB1 as an inhibitor of T cell-mediated antitumor immunity. STUB1 forms a complex with CHIC2, and together, they negatively regulate the expression of cytokine receptors, thereby limiting intratumoral CD8+ T cell numbers and function.
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References
Milling, L. E. et al. Framework for in vivo T cell screens. J. Exp. Med. 221, e20230699 (2024). This paper describes the methods for performing in vivo CD8+ T cell CRISPR screens.
Koochaki, S. H. J. et al. A STUB1 ubiquitin ligase/CHIC2 protein complex negatively regulates the IL-3, IL-5, and GM-CSF cytokine receptor common β chain (CSF2RB) protein stability. J. Biol. Chem. 298, 102484 (2022). A paper detailing cytokine receptor regulation by STUB1 and CHIC2 in myeloid cells.
Apriamashvili, G. et al. Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling. Nat. Commun. 13, 1923 (2022). A paper examining STUB1 in tumor immune evasion.
Bréart, B. et al. IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control. Nature 639, 746–753 (2025). A paper demonstrating the requirement of IL-27 for effective CD8+ T cell-mediated tumor immunity.
LaFleur, M. W. et al. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nat. Immunol. 20, 1335–1347 (2019). This paper describes PTPN2 as an inhibitor of IFNα signaling in the contexts of viral infection and cancer.
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This is a summary of: LaFleur, M. W. et al. A STUB1–CHIC2 complex inhibits CD8+ T cells to restrain tumor immunity. Nat. Immunol. https://doi.org/10.1038/s41590-025-02231-6 (2025).
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CRISPR screens identify STUB1 as an inhibitor of cytokine signaling in CD8+ T cells. Nat Immunol 26, 1436–1437 (2025). https://doi.org/10.1038/s41590-025-02247-y
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DOI: https://doi.org/10.1038/s41590-025-02247-y
