Targeting GOLPH3L improves glioblastoma radiotherapy by regulating STING-NLRP3–mediated tumor immune microenvironment reprogramming
Shuo Sun, Shiyu Qian, Ran Wang, Mengya Zhao, Ran Li, Wei Gu, Mengjie Zhao, Chunfa Qian, Liang Liu, Xianglong Tang, Yangyang Li, Hui Shi, Yaozhu Pan, Hong Xiao, Kun Yang, Chupeng Hu, Yedi Huang, Liangnian Wei, Yuhan Zhang, Jing Ji, Yun Chen, Hongyi Liu
Abstract
Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, the clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that the tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed that GOLPH3L interacted with stimulator of interferon genes (STING) at the aspartic acid residue 184 in Golgi after RT, leading to coat protein complex II-mediated retrograde transport of STING from Golgi to endoplasmic reticulum. This suppressed the STING-NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis, resulting in suppressive TIME, driving GBM resistance to RT. Genetic GOLPH3L ablation in RT-resistant GBM cells augmented antitumor immunity and overcame tumor resistance to RT. Moreover, we have identified a small molecular inhibitor of GOLPH3L, vitamin B5 calcium (VB5), which improved the therapeutic efficacy of RT and immune checkpoint blockade by inducing a robust antitumor immune response in mouse models. Clinically, patients with GBM treated with VB5 exhibited improved responses to RT. Thus, reprogramming the TIME by targeting GOLPH3L may offer a potential opportunity to improve RT in GBM.