NQO1-Mediated Oxidative Stress Resistance and Tumor Microenvironment Remodeling in Glioblastoma

Methods

Proteomics analysis, epigenetic profile by 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 a xenograft murine model were using to investigate the tumor-intrinsic and extrinsic mechanisms to confers resistance to oxidative stress 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, oxidative stress, and the TME. This offers promising new avenues for clinical intervention in GBM.