Targeting KDM4 family epigenetically triggers antitumour immunity via enhancing tumour-intrinsic innate sensing and immunogenicity
© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics..
Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detection, thereby highlighting the potential for pharmacologically targeting epigenetic regulators to restore the impaired immunosurveillance and re-sensitise tumours to immunotherapy. Herein, we demonstrated that KDM4-targeting chemotherapeutic drug JIB-04, epigenetically triggered the tumour-intrinsic innate immune responses and immunogenic cell death (ICD), resulting in impressive antitumour effects. Specifically, JIB-04 induced H3K9 hypermethylation through specific inhibition of the KDM4 family (KDM4A-D), leading to impaired DNA repair signalling and subsequent DNA damage. As a result, JIB-04 not only activated the tumour-intrinsic cyclic GMP-AMP synthase (cGAS)-STING pathway via DNA-damage-induced cytosolic DNA accumulation, but also promoted ICD, releasing numerous damage-associated molecular patterns. Furthermore, JIB-04 induced adaptive resistance through the upregulation of programmed death-ligand 1 (PD-L1), which could be overcome with additional PD-L1 blockade. In human tumours, KDM4B expression was negatively correlated with clinical outcomes, type I interferon signatures, and responses to immunotherapy. In conclusion, our results demonstrate that targeting KDM4 family can activate tumour-intrinsic innate sensing and immunogenicity, and synergise with immunotherapy to improve antitumour outcomes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Clinical and translational medicine - 14(2024), 2 vom: 24. Feb., Seite e1598 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sun, Mayu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 17.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1002/ctm2.1598 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368807479 |
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| 520 | |a Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detection, thereby highlighting the potential for pharmacologically targeting epigenetic regulators to restore the impaired immunosurveillance and re-sensitise tumours to immunotherapy. Herein, we demonstrated that KDM4-targeting chemotherapeutic drug JIB-04, epigenetically triggered the tumour-intrinsic innate immune responses and immunogenic cell death (ICD), resulting in impressive antitumour effects. Specifically, JIB-04 induced H3K9 hypermethylation through specific inhibition of the KDM4 family (KDM4A-D), leading to impaired DNA repair signalling and subsequent DNA damage. As a result, JIB-04 not only activated the tumour-intrinsic cyclic GMP-AMP synthase (cGAS)-STING pathway via DNA-damage-induced cytosolic DNA accumulation, but also promoted ICD, releasing numerous damage-associated molecular patterns. Furthermore, JIB-04 induced adaptive resistance through the upregulation of programmed death-ligand 1 (PD-L1), which could be overcome with additional PD-L1 blockade. In human tumours, KDM4B expression was negatively correlated with clinical outcomes, type I interferon signatures, and responses to immunotherapy. In conclusion, our results demonstrate that targeting KDM4 family can activate tumour-intrinsic innate sensing and immunogenicity, and synergise with immunotherapy to improve antitumour outcomes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Zheng, Jiali |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jingquan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaoguang |e verfasserin |4 aut | |
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