Targeting GOLPH3L improves glioblastoma radiotherapy by regulating STING-NLRP3–mediated tumor immune microenvironment reprogramming
Menée à l'aide de modèles murins et à partir du séquençage de l'ARN d'échantillons tumoraux issus de patients atteints d'un glioblastome, cette étude met en évidence un mécanisme par lequel le blocage de l'interaction entre GOLPH3L et STING améliore l'efficacité de la radiothérapie en supprimant les propriétés immunosuppressives du microenvironnement tumoral
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. GOLPH3L suppressed STING-NLRP3–mediated pyroptosis, resulting in suppressive TIME, driving GBM resistance to RT. Standard of care for glioblastoma (GBM) is surgical resection, radiotherapy (RT), and chemotherapy; however, tumors often relapse because of radioresistance. Here, Sun et al. performed single-cell RNA sequencing on tumors from patients with GBM to identify a suppressive tumor microenvironment contributing to RT resistance. In addition, they identified elevated Golgi phosphoprotein 3 like (GOLPH3L) that was able to be targeted by vitamin B5 calcium (VB5) to improve RT in combination with anti–programmed cell death 1 therapy in mouse models of GBM. They show that, in a retrospective patient cohort, VB5 improves efficacy of RT, which suggests the use of pursuing this in additional patient treatment. —Dorothy Hallberg
https://www.science.org/doi/abs/10.1126/scitranslmed.ado0020 2024