Lactic Acid Promotes TNBC Lung Metastasis via TGF‐β/Smad‐Driven Lipid Metabolic Toxicity and NK Cell Dysfunction

Lactic acid in the tumor microenvironment (TME) drives triple-negative breast cancer (TNBC) progression by coordinately reprogramming lipid metabolism and suppressing immune function. RNA-Seq analysis of lactate-treated MDA-MB-231 and NK-92 cells revealed simultaneous activation of the TGF-β/Smad pathway and upregulation of lipid metabolism genes (FASN, ACSL1). Functionally, lactate treatment increased TGF-β protein levels by approximately 3.5-fold, significantly enhancing TNBC cell invasion (~3-fold) and colony formation (~2.4-fold), while concurrently impairing NK cell cytotoxicity through upregulated PD-1 expression (~3-fold) and suppressed IFN-γ secretion (>60% reduction). These pro-metastatic and immunosuppressive effects were effectively reversed by TGF-β receptor inhibition (SB-431542) or Smad2 knockdown. In mouse xenograft models, lactic acid accelerated tumor growth and increased lung metastatic nodules by ~4-fold, whereas blocking TGF-β signaling reduced tumor burden by approximately 60% and restored NK cell activity. Our findings establish lactic acid as a metabolic-immune regulator that synergistically fuels TNBC metastasis through TGF-β/Smad-mediated lipid reprogramming and immune suppression, offering novel therapeutic targets.