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Peer-reviewedCC BY-NC-NDNature communications

Histone deacetylase inhibition induces an antitumor IRF8-dependent trained immunity-like status in macrophages.

  • Xueting Qin1,2
  • Meida Xiang3
  • Yaqing Guo2
  • Yixin Chang2
  • Zilong Zhang2
  • Jiejie Liu2
  • Xin Zhang2
  • Yuting Pan2
  • Hebing Chen3
  • Weidong Han4,5
  • Jing Nie6
6 affiliations
  1. 1School of Medicine, Nankai University, Tianjin, China.
  2. 2Department of Bio-therapeutic, the First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
  3. 3Academy of Military Medical Sciences, Beijing, China.
  4. 4School of Medicine, Nankai University, Tianjin, China. [email protected].
  5. 5Department of Bio-therapeutic, the First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China. [email protected].
  6. 6Department of Bio-therapeutic, the First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China. [email protected].
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Abstract

Epigenetic reprogramming underlies innate immune memory. However, whether trained immunity can be induced via epigenetic intervention to combat tumors, and the key regulators controlling this process, remain unclear. Here, we demonstrate that histone deacetylase inhibitor (HDACi) priming establishes a trained immunity-like state in monocytes/macrophages, conferring potent antitumor effect in multiple models of triple-negative breast cancer (TNBC) in female mice. Interferon regulatory factor 8 (IRF8) is identified as the master regulator of the inflammatory transcriptional program, which is governed by IRF8-associated super-enhancers and reinforced by HDACi. Myeloid-specific IRF8 deficiency impairs pro-inflammatory macrophage differentiation and abrogates HDACi-induced antitumor efficacy. Moreover, an IRF8-driven, CCL8-expressing macrophage subset recruits and activates cytotoxic CCR5⁺CD8⁺ T cells in the TNBC microenvironment. As a proof-of-principle with translational relevance, CCL8-overexpressing EGFR-targeted CAR T cells exhibit enhanced trafficking and improved efficacy in a humanized TNBC model. Our study defines the IRF8-CCL8-CCR5 axis as an epigenetically potentiated nexus of innate and adaptive antitumor immunity.

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Cite

BibTeXRIS
BibTeX
@article{qin2026histone,
  title = {{Histone deacetylase inhibition induces an antitumor IRF8-dependent trained immunity-like status in macrophages.}},
  author = {Xueting Qin and Meida Xiang and Yaqing Guo and Yixin Chang and Zilong Zhang and Jiejie Liu and Xin Zhang and Yuting Pan and Hebing Chen and Weidong Han and Jing Nie},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77904-3},
  url = {https://europepmc.org/article/MED/42907426},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Histone deacetylase inhibition induces an antitumor IRF8-dependent trained immunity-like status in macrophages.
AU  - Xueting Qin
AU  - Meida Xiang
AU  - Yaqing Guo
AU  - Yixin Chang
AU  - Zilong Zhang
AU  - Jiejie Liu
AU  - Xin Zhang
AU  - Yuting Pan
AU  - Hebing Chen
AU  - Weidong Han
AU  - Jing Nie
PY  - 2026
DA  - 2026/09/22
JO  - Nature communications
DO  - 10.1038/s41467-026-77904-3
UR  - https://europepmc.org/article/MED/42907426
AB  - Epigenetic reprogramming underlies innate immune memory. However, whether trained immunity can be induced via epigenetic intervention to combat tumors, and the key regulators controlling this process, remain unclear. Here, we demonstrate that histone deacetylase inhibitor (HDACi) priming establishes a trained immunity-like state in monocytes/macrophages, conferring potent antitumor effect in multiple models of triple-negative breast cancer (TNBC) in female mice. Interferon regulatory factor 8 (IRF8) is identified as the master regulator of the inflammatory transcriptional program, which is governed by IRF8-associated super-enhancers and reinforced by HDACi. Myeloid-specific IRF8 deficiency impairs pro-inflammatory macrophage differentiation and abrogates HDACi-induced antitumor efficacy. Moreover, an IRF8-driven, CCL8-expressing macrophage subset recruits and activates cytotoxic CCR5⁺CD8⁺ T cells in the TNBC microenvironment. As a proof-of-principle with translational relevance, CCL8-overexpressing EGFR-targeted CAR T cells exhibit enhanced trafficking and improved efficacy in a humanized TNBC model. Our study defines the IRF8-CCL8-CCR5 axis as an epigenetically potentiated nexus of innate and adaptive antitumor immunity.
SN  - 2041-1723
ER  -