2. Academic Validation
  3. TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation

TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation

  • Nat Commun. 2023 May 26;14(1):3050. doi: 10.1038/s41467-023-38784-z.
Yu-Hsuan Chen # 1,  Han-Hsiun Chen # 1,  Won-Jing Wang 2,  Hsin-Yi Chen 3,  Wei-Syun Huang 2,  Chien-Han Kao 1 2,  Sin-Rong Lee 1 4,  Nai Yang Yeat 1 5 6,  Ruei-Liang Yan 1,  Shu-Jou Chan 1,  Kuen-Phon Wu 1 4,  Ruey-Hwa Chen 7 8
Affiliations

Affiliations

  • 1 Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan.
  • 2 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 3 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.
  • 4 Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, 106, Taiwan.
  • 5 Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan.
  • 6 Department of Chemistry, National Tsing Hua University, Hsinchu, 300, Taiwan.
  • 7 Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan. [email protected].
  • 8 Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, 106, Taiwan. [email protected].
  • # Contributed equally.
PMID: 37237031 DOI: 10.1038/s41467-023-38784-z
Abstract

Activation of tumor-intrinsic innate immunity has been a major strategy for improving immunotherapy. Previously, we reported an autophagy-promoting function of the deubiquitinating Enzyme TRABID. Here, we identify a critical role of TRABID in suppressing anti-tumor immunity. Mechanistically, TRABID is upregulated in mitosis and governs mitotic cell division by removing K29-linked polyubiquitin chain from Aurora B and Survivin, thereby stabilizing the entire chromosomal passenger complex. TRABID inhibition causes micronuclei through a combinatory defect in mitosis and Autophagy and protects cGAS from autophagic degradation, thereby activating the cGAS/STING innate immunity pathway. Genetic or pharmacological inhibition of TRABID promotes anti-tumor immune surveillance and sensitizes tumors to anti-PD-1 therapy in preclinical Cancer models in male mice. Clinically, TRABID expression in most solid Cancer types correlates inversely with an interferon signature and infiltration of anti-tumor immune cells. Our study identifies a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and highlights TRABID as a promising target for sensitizing solid tumors to immunotherapy.

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