PGAM1 Orchestrates Cell Cycle Progression, Glycolytic Reprogramming, and Immunosuppressive Microenvironment in...

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by uncontrolled cell cycle progression, profound metabolic reprogramming, and immune evasion, yet effective therapeutic targets remain limited. In this study, we integrated bulk and single-cell transcriptomic analyses to identify phosphoglycerate mutase 1 (PGAM1) as a central regulator of TNBC progression. Functional assays revealed that PGAM1 is significantly upregulated in TNBC tissues and cell lines, particularly associated with enhanced G2/M phase activity. Silencing PGAM1 suppressed TNBC cell proliferation and migration and induced cell cycle arrest at the G2/M phase. Mechanistically, PGAM1 knockdown impaired glycolytic flux by reducing the activity of rate-limiting enzymes, attenuating pyruvate entry into the TCA cycle, and consequently diminishing lactate production. Notably, this metabolic disruption extended beyond tumor-intrinsic effects: reduced lactate secretion inhibited M2-type tumor-associated macrophage polarization in co-culture systems, thereby alleviating immunosuppressive signaling in the tumor microenvironment. These findings highlight PGAM1 as a critical node linking three cancer hallmarks-cell cycle dysregulation, metabolic reprogramming, and immune evasion. By bridging intracellular metabolic control with immune modulation via lactate signaling, PGAM1 emerges as a promising therapeutic target that could simultaneously inhibit TNBC cell proliferation and remodel the tumor immune landscape.