Abstract

Immune checkpoint blockade targeting the PD-1/PD-L1 axis shows promise in triple-negative breast cancer (TNBC), yet durable responses are limited by immune escape. Here, we identified tumor-derived bromodomain-containing protein 4 (BRD4) as a critical mediator of tumor-associated macrophage (TAMs)-driven immune evasion in TNBC. Using syngeneic TNBC mouse models, we found that BRD4 promotes PD-L1 expression on TAMs by increasing GM-CSF production from tumor cells. Mechanistically, BRD4 binds to the GM-CSF promoter enriched with H4K8 lactylation (H4K8La) and H3K27 acetylation (H3K27Ac). BRD4 further sustains pyruvate and lactate pools via upregulation of PKM2, thereby amplifying H4K8La and H3K27Ac on the basis of modifications at the GM-CSF locus. Functionally, exogenous GM-CSF supplementation rescued impaired tumor growth and defective activation of TAMs caused by BRD4 inhibition, establishing a direct BRD4-GM-CSF-TAMs regulatory axis. Therapeutically, combined treatment with the BRD4 inhibitor JQ1 or the first bromodomain (BD1) selective inhibitor MS402 and an anti-GM-CSF antibody markedly suppressed TNBC progression and converted the tumor immune microenvironment from “cold” to “hot”. In conclusion, our study reveals a previously unrecognized metabolic-epigenetic mechanism through which BRD4 drives GM-CSF-dependent TAMs activation and immune evasion in TNBC. Targeting BRD4 in combination with GM-CSF blockade represents a promising therapeutic strategy to overcome immune resistance in this aggressive breast cancer subtype.