Extracellular vesicles derived from fetal stem cells in early pregnancy modulate glycolysis and lipid metabolism to induce apoptosis in cancer cells.

Glycolytic dependency in solid tumors underlies resistance to current therapies. We developed antitumoral fetal stem cell-derived extracellular vesicles (itAT-FSC-EVs) using an ex vivo multistage conditioning workflow to enhance their metabolism-modulating capacity and evaluated their effects in cellular and animal models. In colorectal (HCT116) and hepatic (HepG2) cancer cells, itAT-FSC-EVs reduced lactate release and downregulated pyruvate dehydrogenase kinase 1, indicating pyruvate influx into mitochondria. This was accompanied by reduced glycolytic activity, increased oxygen consumption, and elevated mitochondrial membrane potential. Reactive oxygen species accumulated and contributed to cytotoxicity, culminating in apoptosis, whereas normal HEK293 cells remained viable with transient oxidative stress. Cancer cells exhibited suppression of lipogenic genes, including fatty acid synthase, reduced mitochondrial mass and a sustained increase in the NADP/NADPH ratio, indicating impaired redox buffering despite enhanced respiration. In HCT116 xenografts, systemic itAT-FSC-EV administration reduced tumor growth and lowered pyruvate dehydrogenase kinase 1 and fatty acid synthase levels, supporting a metabolic reset in vivo. These findings indicate that itAT-FSC-EVs reprogram malignant cells from glycolytic dependence toward mitochondrial oxidative metabolism, disrupt redox homeostasis, and induce cell death. This approach may synergistically modulate the tumor niche with immunotherapy by lowering lactate production, an immunosuppressive factor in solid tumors. Thus, itAT-FSC-EVs represent a metabolism-rewiring biological system with translational potential for normalizing tumor metabolism and complementing existing anticancer modalities.