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

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.