Histone lactylation bridges metabolic reprogramming with chromatin-immune crosstalk in triple-negative breast cancer.

Breast cancer (BC) is the most common cancer in women, and triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype, often characterized by metabolic dysregulation and immune evasion. Recent studies have linked enhanced glycolysis and metabolic reprogramming to TNBC malignancy. Histone lactylation, a novel modification derived from lactate, connects metabolism with gene regulation. This study unveils its pivotal role in promoting TNBC progression and reshaping the tumor immune microenvironment using single-cell genomics, multi-omics, and clinical cohorts. Glycolysis-related genes are enriched in TNBC cells, with elevated lactate dehydrogenase A (LDHA) correlating with poor prognosis and increased histone lactylation. Inhibiting glycolysis reduces histone lactylation, suppressing tumor growth and metastasis. Mechanistically, lactate-derived histone lactylation enhances chromatin accessibility and drives oncogene transcription. Additionally, histone lactylation cooperates with active transcription-associated histone marks, such as H3K27ac, to further promote chromatin accessibility, thereby reprogramming the tumor's epigenetic landscape. Site-specific lactylation at H3K9la, H3K14la and H3K18la regulates distinct malignant traits. Single-cell immune profiling reveals lactylation-dependent immune cell states, underscoring its role in immune modulation. Furthermore, glycolysis-driven histone lactylation in TNBC is closely associated with the modulation of tumor immune responses and the regulation of immune-related pathways. Overall, histone lactylation links metabolic reprogramming to gene regulation. By modulating tumor progression and immune responses, histone lactylation emerges as a promising therapeutic target for improving TNBC management and patient outcomes.