4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 14, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-023-38784-z

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Activation of tumor-intrinsic innate immunity is crucial for improving immunotherapy. The deubiquitinating enzyme TRABID is found to play a suppressive role in anti-tumor immunity by regulating mitotic cell division and activating the cGAS/STING pathway. TRABID inhibition induces micronuclei and protects cGAS from autophagy, thus promoting anti-tumor immune responses.
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. cGAS/STING activation is linked to the induction of anti-tumor immune responses. Here the authors report a role for the deubiquitinating enzyme TRABID in regulating mitotic cell division and suppressing anti-tumor immunity, suggesting that TRABID inhibition induces micronuclei and activates cGAS/STING pathway.

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