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
  • 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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