UCP2 in Glioblastoma Cells Regulates Mitochondrial Metabolic Reprogramming to Mediate Immunophenotypic Repolarization of Tumor-Associated Macrophages and Immunotherapy.

This paper sought to determine whether uncoupling protein 2 (UCP2) regulates the immune phenotype of TAMs by modulating its own mitochondrial metabolic homeostasis in glioblastoma (GBM) cells, thereby influencing anti-tumor treatment response. This study evaluated UCP2 levels in clinical GBM samples and cell lines based on public databases, immunohistochemistry, RT-qPCR, and Western blot. A cell model with specific knockdown of UCP2 was constructed, and cell proliferation, migration and invasion, and apoptosis were detected. ATP measurement, Seahorse analysis, JC-1 staining, H2DCFDA, and MitoSOX staining were employed to assess mitochondrial metabolic function and ROS levels in GBM cells. A GBM-THP-1 co-culture system was established to evaluate the impact of UCP2 knockdown in GBM cells on macrophage polarization. A subcutaneous tumor model was established to evaluate the synergistic effect of UCP2 silencing + anti-PD-L1 therapy. UCP2 was upregulated in GBM tissues and accompanied by increased infiltration of M2-type TAMs. Specific knockdown of UCP2 in GBM cells inhibited cell proliferation and invasion, promoted apoptosis, and induced metabolic reprogramming by inhibiting mitochondrial energy metabolism, reducing mitochondrial membrane potential, and ROS accumulation. Co-culture with GBM cells with UCP2 knockdown promoted macrophage polarization toward the M1 type. UCP2 knockdown + anti-PD-L1 antibody inhibited GBM growth and increased the infiltration of M1-type TAMs. Knockdown of UCP2 in GBM cells reshapes the tumor microenvironment by regulating the tumor cell mitochondrial metabolism, thereby influencing their interaction with TAMs. This promotes M1-type repolarization and enhances the efficacy of anti-tumor treatment, making it a potential therapeutic target.