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

Yu-Hsuan Chen, Han-Hsiun Chen, Won-Jing Wang, Hsin-Yi Chen, Wei-Syun Huang, Chien-Han Kao, Sin-Rong Lee, Nai Yang Yeat, Ruei-Liang Yan, Shu-Jou Chan, Kuen-Phon Wu and Ruey-Hwa Chen ()
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Yu-Hsuan Chen: Academia Sinica
Han-Hsiun Chen: Academia Sinica
Won-Jing Wang: National Yang Ming Chiao Tung University
Hsin-Yi Chen: Taipei Medical University
Wei-Syun Huang: National Yang Ming Chiao Tung University
Chien-Han Kao: Academia Sinica
Sin-Rong Lee: Academia Sinica
Nai Yang Yeat: Academia Sinica
Ruei-Liang Yan: Academia Sinica
Shu-Jou Chan: Academia Sinica
Kuen-Phon Wu: Academia Sinica
Ruey-Hwa Chen: Academia Sinica

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38784-z

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