A novel hypoxic tumor microenvironment signature for predicting the survival, progression, immune responsiveness and chemoresistance of glioblastoma: a multi-omic study

The hypoxic tumor microenvironment (TME) was reported to promote the aggressive phenotype, progression, recurrence, and chemoresistance of glioblastoma (GBM). We developed and validated a hypoxia gene signature for individualized prognostic prediction in GBM patients. In total, 259 GBM-specific hypoxia-related genes (HRGs) were obtained in hypoxic cultured GBM cells compared with normoxic cells. By applying the k-means algorithm, TCGA GBM patients were divided into two subgroups, and the patients in Cluster 1 exhibited high HRG expression patterns, older age, and poor prognosis, which was validated in the CGGA cohort. Cox regression analyses were performed to generate an HRG-based risk score model consisting of five HRGs, which could reliably discriminate the overall survival (OS) and progression-free survival (PFS) of high- and low-risk patients in both the TCGA training and CGGA validation cohorts. Then, nomograms with the hypoxia signature for OS and PFS prediction were constructed for individualized survival prediction, better treatment decision-making, and follow-up scheduling. Finally, functional enrichment, immune infiltration, immunotherapy response prediction and chemotherapy resistance analyses demonstrated the vital roles of the hypoxic TME in the development, progression, multitherpy resistance of GBM. The hypoxia gene signature could serve as a promising prognostic predictor and potential therapeutic target to combat chemoresistant GBM.