Developing and validating a prognostic disulfidptosis-related signature for glioblastoma: predicting radioresistance and synergestic effect with immunotherapy

Programmed cell death (PCD) modulated radioresistance is one of the predominant causes of treatment failure in glioblastoma (GBM). Disulfidptosis, a newly discovered form of PCD, plays a crucial role in GBM progression. However, the association among disulfidptosis, radiosensitivity and radiotherapy (RT) in GBM remain unclear.

We systematically analyzed disulfidptosis-related genes in 1075 GBM patients and constructed a disulfidptosis-related gene signature (DRS). Correlations among the DRS, patient prognosis and immune microenvironment were fully explored. The effects of DRS and EFEMP2 on radiotherapy efficacy were investigated via single cell sequencing analysis and validated via in vitro and in vivo experiments.

The DRS was identified as a robust and independent prognostic biomarker for GBM by multivariate Cox regression analysis, receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) in multiple cohorts. High DRS is characterized by radioresistance, and EFEMP2 was proven to be the key gene involved in this process by single cell sequencing analysis, CCK-8 assay and a clonogenic survival assay. In high-DRS patients, the cancer-immunity cycle is attenuated because the antitumor cytotoxicity of CD8+ T cells is inhibited by immune checkpoints. Preclinically, the overexpression of EFEMP2 induced radioresistance and enhancing the efficacy of programmed cell death ligand-1 (PD-L1) blockade in GL261-bearing mice. The combination of irradiation and anti-PD-L1 therapy had a synergistic effect on GBM murine models in which EFEMP2 was overexpressed.

Our study bioinformatically and experimentally reveals the molecular landscape of disulfidptosis in GBM, develops a predictive signature for predicting prognosis as well as radioresistance, and provides a synergistic treatment that combines radiotherapy with immunotherapy for radioresistant GBM patients with high DRS or EFEMP2 expression.