Single-cell analysis reveals corticosteroid-associated impairment of tumor-infiltrating NK cells in glioblastoma patients

Abstract Glioblastoma is the most common and aggressive malignant primary brain tumor in adults, characterized by poor prognosis and limited response to current therapeutic strategies. Corticosteroids, particularly dexamethasone, are widely used in clinical practice to control symptomatic peritumoral edema, yet they exert profound immunosuppressive effects whose impact on tumor-infiltrating NK cells remains poorly defined. To address this issue, we analyzed a publicly available single-cell RNA sequencing dataset of CD45⁺ cells isolated from five IDH-wildtype glioblastomas, including two patients undergoing perioperative dexamethasone treatment and three untreated patients, alongside two non-tumor brain samples. Our results suggested that perioperative dexamethasone exposure was associated with a reshaped intratumoral NK cell landscape, characterized by a relative enrichment of CD56 bright subsets. Perioperative corticosteroid treatment was also associated with transcriptional features consistent with impaired NK cell effector programs, as evidenced by reduced cytotoxicity and inflammation scores, down-regulation of granzymes, perforin, pro-inflammatory cytokines, and activating receptors, and concomitant upregulation of inhibitory molecules. Gene set enrichment analysis further demonstrated strong downregulation of NK cell-mediated cytotoxicity and cell-killing pathways. Together with previous evidence of corticosteroid-associated impairment of glioma-infiltrating dendritic cells, these findings suggest that perioperative steroid therapy may affect both cytotoxic and antigen-presenting innate compartments. If confirmed in larger patient cohorts, these observations may support the importance of minimizing steroid exposure to optimize immunotherapeutic efficacy.