NAD(P)H: quinone oxidoreductase 1-mediated oxidative stress resistance and tumor microenvironment remodeling in glioblastoma

BACKGROUND: Glioblastoma (GBM) is a highly aggressive brain tumor, with glioblastoma stem cells (GSCs) occupying the pinnacle of a complex tumor microenvironment (TME), conferring therapeutic resistance. The TME plays a role in tumor development by creating a niche rich in reactive oxygen species (ROS) through oxidative stress (OS). Here, we identified NAD(P)H: quinone oxidoreductase 1 (NQO1) as an essential regulatory factor in antioxidant stress response, which is key to maintaining GSCs and the immunosuppressive TME. METHODS: Proteomics analysis and epigenetic profiling using H3K27ac ChIP-sequencing and single-cell RNA sequencing were performed to define the high enrichment of NQO1 in GBM. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of NQO1 in GSC proliferation and self-renewal. Patient-derived GSCs and xenograft murine models were using to investigate the tumor-intrinsic and extrinsic mechanisms to confers resistance to OS and reprogram the immunosuppressive TME. RESULTS: NQO1 was preferentially expressed in GSCs and regulated ROS levels, preserving the stability of nuclear Lamin B1 and inhibiting cGAS-type I interferon signaling, which helps to remodel the immunosuppressive TME. Furthermore, nuclear factor erythroid 2-related factor 2 (NRF2) transcriptionally regulates NQO1, suppressing type I interferon signaling. CONCLUSIONS: NQO1 plays critical roles at both the cell-autonomous and cell-extrinsic levels for clinical treatment. Targeting NQO1 and its downstream signaling pathways, including β-lapachone and immune checkpoint inhibitors such as anti-PD-1 therapy, enhances our understanding of the interactions between GSCs, OS, and the TME. This offers promising new avenues for clinical intervention in GBM.