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A STUB1-CHIC2 complex inhibits CD8+ T cells to restrain tumor immunity

Martin W LaFleur1,2, Lauren E Milling3,4, Priyamvada Prathima3,4

  • 1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. martin_lafleur@hms.harvard.edu.

Nature Immunology
|August 12, 2025
PubMed

Insights

Scientists discovered STUB1 as a negative regulator of anti-tumor CD8+ T cell function. Inhibiting the STUB1-CHIC2 pathway enhances CD8+ T cell immunity against cancer.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • In vivo CRISPR screens in CD8+ T cells have identified cancer immunotherapy targets.
  • A limited portion of the genome has been annotated, indicating potential for new discoveries.

Purpose of the Study:

  • To identify novel regulators of anti-tumor CD8+ T cell function.
  • To investigate the role of the E3 ubiquitin ligase STUB1 in CD8+ T cell-mediated anti-tumor immunity.

Main Methods:

  • Conducted in vivo CRISPR screens in CD8+ T cells responding to murine melanoma.
  • Assessed the function of 899 genes in CD8+ T cells.
  • Utilized knockout models (Stub1 knockout CD8+ T cells) to evaluate tumor growth control.
  • Investigated the molecular mechanism involving STUB1, CHIC2, and cytokine receptor expression.

Main Results:

  • Identified STUB1 as a novel negative regulator of anti-tumor CD8+ T cell function.
  • Demonstrated that Stub1 knockout CD8+ T cells effectively control tumor growth in multiple murine models.
  • Elucidated that STUB1 interacts with CHIC2 to modulate cytokine receptor expression in both mouse and human CD8+ T cells.
  • Found that the interleukin-27 receptor α is critical for tumor growth control in Stub1/Chic2 knockout CD8+ T cells.

Conclusions:

  • The STUB1-CHIC2 complex regulates cytokine receptor expression in CD8+ T cells.
  • Inhibiting the STUB1-CHIC2 pathway offers a therapeutic strategy to enhance CD8+ T cell-mediated anti-tumor immunity.

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