Metabolic Reprogramming Enhances NK Cell Therapy Against Glioblastoma
Tsung-I Hsu, Taipei Medical University
Glioblastoma (GBM), a highly aggressive brain tumor, presents significant challenges due to its therapeutic resistance and immune evasion mechanisms. This study explores a novel combination therapy involving progesterone (Prog) and abiraterone (Abi) to enhance natural killer (NK) cell-mediated anti-tumor activity through metabolic reprogramming and immune modulation. We demonstrate that Prog profoundly alters GBM metabolism by suppressing glucose utilization, reducing key metabolites such as glucose, pyruvate, and UDP-GlcNAc, and impairing mitochondrial respiration. Prog also inhibits sialylation by downregulating enzymes such as ST8SIA5 and ST3GAL5, leading to reduced sialylation of NK ligands on GBM cells. These effects enhance NK cell recognition and cytotoxicity. Importantly, the combination of Prog and Abi significantly extended survival in mouse models. C57BL/6 mice with intact immune systems exhibited improved outcomes compared to Scid mice lacking NK cells, indicating immunomodulatory effect or Prog. Single-cell RNA sequencing revealed that Prog increased NK cell infiltration and activation, with elevated expression of markers such as NKG7 and KLRK1. Furthermore, Prog reduced the expression of MGMT, a key player in GBM resistance to temozolomide, and synergized with Abi to inhibit tumor growth and prolong survival. This study highlights the transformative potential of combining metabolic reprogramming and immune modulation to overcome TMZ resistance in GBM. By integrating innovative NK cell therapy with targeted metabolic interventions, this research offers a promising pathway to significantly improve therapeutic outcomes for GBM patients.