<p>Metabolic reprogramming and immune regulation are tightly interconnected processes that critically influence cancer progression. The efficacy of immunotherapy is limited in triple-negative breast cancer (TNBC) by metabolic abnormality and immunosuppressive microenvironment. However, the molecular mechanisms through which these alterations cooperate to drive immune evasion and tumor progression in TNBC remain poorly defined. Through transcriptomic profiling, we identified glycolysis and chemokine signaling as the dominant intersecting metabolic and immune pathways that distinguish TNBC from non-TNBC subtypes. Phosphoglycerate kinase 1 (PGK1) is associated with poor prognosis and with myeloid-derived suppressor cells (MDSCs), acting as a key metabolic node linking metabolic regulation to immune modulation. Functionally, PGK1 knockdown inhibited tumor growth in vitro and in vivo and reduced MDSC recruitment. Notably, PGK1 knockdown exerted a more pronounced antitumor effect under immune surveillance, accompanied by decreased infiltration of both monocytic and polymorphonuclear MDSCs and recovered CD8⁺ T cell function. Mechanistically, PGK1 increased lactate production and global lysine lactylation. Notably, histone H3 lysine 18 lactylation (H3K18la) at the CCL5 promoter served as a dominant and required epigenetic modification for PGK1-driven CCL5 transcription, thereby driving CCL5-dependent MDSC recruitment. P300 and class I HDACs were identified as candidate “writer” and “eraser” enzymes for PGK1-dependent H3K18la modification. Notably, combining the PGK1 inhibitor ABT-E79 with anti-PD-1 therapy synergistically decreased MDSC infiltration, recovered CD8⁺ T cell function, and elicited superior antitumor responses compared to monotherapy. Collectively, this study shows a mechanistic link between metabolic reprogramming and immune evasion, offering new therapeutic insights for TNBC.</p><p></p>