Lactate-driven metabolic–epigenetic reprogramming in breast cancer: immune evasion and therapeutic resistance

Abstract Background Breast cancer develops within a metabolically heterogeneous tumor microenvironment characterized by regional hypoxia, glycolytic activation, lactate accumulation, extracellular acidification, and impaired antitumor immunity. Lactate is now recognized not only as a metabolic end product, but also as a transported substrate, a receptor ligand, and a potential source of lysine lactylation. Main body In this Review, we summarize current evidence on lactate production, MCT1/MCT4-dependent trafficking, GPR81/HCAR1-mediated sensing, immune remodeling, and metabolic–epigenetic regulation in breast cancer. We organize these effects into three interconnected layers. First, extracellular acidification, nutrient competition, and redox stress produce rapid and potentially reversible suppression of CD8⁺ T cells, natural killer cells, and dendritic cells. Second, sustained lactate-rich conditions alter the relative fitness of immune and stromal populations, weakening cytotoxic effectors while supporting regulatory T cells, tumor-associated macrophages, suppressive myeloid populations, and stromal immune exclusion. Third, histone and non-histone lactylation, together with RNA-level and chromatin regulatory mechanisms, may contribute to more durable state fixation. We distinguish direct breast cancer evidence from mechanisms established in other cancers and from transcriptome-based lactylation-associated signatures. We also discuss methodological limitations, subtype-specific evidence, and therapeutic strategies targeting lactate production, transport, sensing, and downstream epigenetic regulation. Short conclusion Lactate-driven metabolic and epigenetic regulation provides a useful framework for understanding immune evasion and therapeutic resistance in breast cancer. However, direct mechanistic evidence remains concentrated in triple-negative breast cancer and tumor-intrinsic phenotypes. Lactylation should therefore be considered a candidate mechanism of durable state fixation rather than a universal explanation for lactate-associated effects. Future studies integrating direct lactylation measurements, spatial multi-omics, functional perturbation, and patient-derived models will be required to define clinically actionable lactate-dependent states.