Clinical and Biological Significance of a Necroptosis-Related Gene Signature in Glioma.

Background: As a novel form of programmed cell death, necroptosis is related to multiple tumor types and their immune microenvironments. However, its association with glioma has not been clarified.

Methods: Necroptosis genes were obtained from the Gene Set Enrichment Analysis (GSEA) database. RNA-seq and clinical data were downloaded from TCGA and CGGA databases. A necroptosis gene signature was constructed based on univariate and multivariate Cox regression analyses. Next, survival analysis, independent prognostic analysis, and nomogram were performed to assess and verify the model. Subsequently, we analyzed the tumor microenvironment (TME) and immune cell infiltration ESTIMATE and CIBERSORTx algorithms. Finally, the response of glioma patients in the TCGA database to immune checkpoint inhibitor (ICI) therapy was predicted using the Tumor Immune Dysfunction and Exclusion (TIDE) database.

Results: Of the seven prognostic necroptosis genes, RIPK1, RIPK3, FAS, and FADD were used to construct the risk signature that accurately predicts the prognosis of glioma patients. Functional enrichment results suggest that necroptosis is correlated with immune response and angiogenesis. Immune analysis revealed that necroptosis can boost inflammatory activity and attract immunosuppressive cell infiltration to form a chronic inflammatory microenvironment, promoting glioma growth. Additionally, glioma patients in the TCGA cohort with high necroptosis gene expression exhibited a better response to ICI therapy predicted by the TIDE algorithm.

Conclusion: We constructed a necroptosis gene signature, which has the potential for use as a biomarker for predicting glioma patients' prognosis, revealing the association between necroptosis and the immune microenvironment, and serving as a reference for immune therapy.