Recently, a research team led by Associate Professor Qian Zhang from the School of Basic Medical Sciences published apaper entitled “NQO1-mediated oxidative stress resistance and tumor microenvironment remodeling in glioblastoma” in Neuro-Oncology.
This study identified NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical molecule for oxidative stress resistance and tumor microenvironment remodeling in glioblastoma. The research revealed that NQO1 maintains Lamin B1 stability in glioblastoma stem cells (GSCs) through the ROS–Lamin B1 signaling axis, thereby suppressing cGAS–STING signaling and type I interferon secretion and promoting an immunosuppressive tumor microenvironment. Targeting NQO1 and its downstream signaling effectors, such as β-lapachone combined with the immune checkpoint therapy with anti-PD-1, can simultaneously dismantle oxidative stress resistance and reshape the immune microenvironment, providing new insights for clinical translational therapy of glioblastoma.
Glioblastoma (GBM) is the most lethal primary malignant tumor of the central nervous system. Despite multimodal treatment with surgery, radiotherapy, and chemotherapy, median survival remains difficult to extend beyond two years. The aggressive nature of GBM is closely linked to its highly complex tumor microenvironment (TME). Glioblastoma stem cells (GSCs) occupy a central position within this microenvironment. With their capacities for self-renewal, multilineage differentiation, and tumor initiation, they are regarded as a major driver of tumor recurrence and therapeutic resistance. Furthermore, oxidative stress induced by acidosis, nutrient deprivation, hypoxia, and immune infiltration leads to chronic reactive oxygen species (ROS) overload, driving DNA damage, lipid peroxidation, and metabolic reprogramming. Understanding how GSCs exploit these conditions to reinforce their antioxidant systems and interact with immune cells within the TME to preserve their stemness and evade immune surveillance remains to be elucidated.
By integrating proteomic and single-cell transcriptomic data, this study identified NQO1 as a core molecule supporting the antioxidant advantage of GSCs. In oxidative stress models induced by hydrogen peroxide and tert-butyl hydroperoxide, GSCs showed strong resistance to oxidative stress. NQO1 prevents oxidative stress by maintaining ROS homeostasis, which protects tumor cells and supports the stability of nuclear Lamin B1, preventing nuclear envelope rupture. Inhibition of NQO1 induced the extensive leakage of dsDNA into the cytoplasm, strongly activating the cGAS-STING pathway, increasing Type I interferon secretion, and enhancing CD8+ T cell infiltration within the TME. Mechanically, NRF2 transcriptionally regulates NQO1, which further suppresses cGAS-STING signaling and remodels the immunosuppressive TME, enabling tumor cells to evade immune surveillance and attack. Based on these findings, the researchers utilized the NQO1 substrate β-lapachone in combination with anti-PD-1 monoclonal antibody, which synergistically enhanced CD8+ T cell infiltration cytotoxicity, providing novel clinical translational evidence for GBM immunotherapy.
Associate Professor Qian Zhang, from the School of Basic Medical Sciences, Nanjing Medical University (NMU), and Professor Chaojun Li, from the State Key Laboratory of Reproductive Medicine and Offspring Health, NMU are co-corresponding authors of this paper. Yangqing Li, PhD student from Nanjing University, Tao Kang, Zhen Jia and Gaoyuan Cui, graduate students from NMU, Chenfei Lu, PhD from the Department of Neurosurgery at the First Affiliated Hospital of NMU, are the co-first authors.
This work was supported by the National Natural Science Foundation of China (Youth Science Fund Program A, General Program, and Young Scientists Fund), the Clinical Research Foundation for the Prevention and Treatment of Collaborative Innovation Center for Cancer Personalized Medicine, and the Natural Science Foundation of Jiangsu Province.
Link to the original article: https://doi.org/10.1093/neuonc/noag015
(Drafted by Associate Professor Qian Zhang’s Team; Reviewed by Feng Chen & Juejin Wang; Translation revised by Wenbo Wu)
