Integrated PANoptosis Profiling Identifies Immunosuppressive Subtypes and a Prognostic Signature With Functional Validation of MLKL in Glioblastoma
ABSTRACT Objective The prognosis of glioblastoma (GBM) remains highly unfavorable, largely due to high tumor heterogeneity and an immunosuppressive microenvironment. However, the functional role of PANoptosis in this context is poorly understood. Methods Patients were stratified via K‐means clustering. A risk score model was constructed using prognosis‐associated genes identified by Cox regression and validated in independent cohorts. Immune infiltration was analyzed using CIBERSORT and ESTIMATE. Single‐cell RNA sequencing (scRNA‐seq) profiled the tumor microenvironment. Functional assays were performed following MLKL knockdown. Result Two molecular subtypes based on PANoptosis‐related genes were identified, with distinct survival and immune features. A five‐gene (MLKL, YWHAG, GZMB, ELANE, CASP4) risk score served as an independent prognostic factor. The high‐risk group exhibited an inflamed yet dysfunctional tumor immune microenvironment, marked by higher PD‐L1 expression, T cell dysfunction, and Merck18 score. scRNA‐seq confirmed elevated activity of PANoptosis in GBM. Finally, MLKL knockdown was shown to suppress malignant phenotypes and induce apoptosis. Conclusion Our findings link PANoptosis to GBM heterogeneity, providing a prognostic model and nominating MLKL as a key functional mediator, which may inform patient stratification and the development of targeted therapies.