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

• Published in: Nature communications 2023-05, Vol.14 (1), p.3050-3050, Article 3050
• Main Authors: Chen, Yu-Hsuan, Chen, Han-Hsiun, Wang, Won-Jing, Chen, Hsin-Yi, Huang, Wei-Syun, Kao, Chien-Han, Lee, Sin-Rong, Yeat, Nai Yang, Yan, Ruei-Liang, Chan, Shu-Jou, Wu, Kuen-Phon, Chen, Ruey-Hwa
• Format: Article
• Language: English
• Subjects: 13; 13/31; 13/95; 14/19; 38/32; 38/77; 49; 631/67/327; 631/80/39/2346; 631/80/641/1655; 692/699/67/580; 82/51; 82/58; 96; 96/1; Animal models; Animals; Aurora B protein; Autophagy; Cancer; Cell division; Enzymes; Humanities and Social Sciences; Immune response; Immune system; Immunity, Innate; Immunosurveillance; Immunotherapy; Innate immunity; Male; Metastases; Mice; Micronuclei; Mitosis; multidisciplinary; Neoplasms - drug therapy; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; PD-1 protein; Science; Science (multidisciplinary); Sensitizing; Solid tumors; Survivin; Tumors; Ubiquitin-Specific Proteases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38784-z

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.