A cell death program-based tumor signature stratifies prognosis, immune landscape, and therapeutic response in glioma.

Background: Glioma exhibits profound intratumoral heterogeneity driven by coordinated cell death programs and dynamic tumor-microenvironment interactions. However, the transcriptional landscape linking inflammatory cell death signatures with malignant cell states, genomic alterations, and therapeutic vulnerability remains incompletely defined. We sought to develop a prognostic cell death-associated signature and elucidate its biological and clinical relevance in glioma. Methods: Using transcriptomic and clinical data from TCGA-GBMLGG and external validation cohorts, we constructed a pyroptosis-apoptosis-associated gene signature (PA.Sig) through integrative survival modeling. Genomic alteration profiling, pathway enrichment analyses, and tumor immune microenvironment characterization were performed. Single-cell RNA sequencing datasets were analyzed to delineate malignant cell states and intercellular communication patterns. Functional validation was conducted in glioma cell lines treated with chemotherapeutic agents. Results: PA.Sig stratified patients into high- and low-risk groups with significantly different overall survival and independent prognostic value. High-risk tumors were characterized by increased somatic mutation burden, enrichment of cell cycle and inflammatory pathways, and a malignant-centered outgoing signaling architecture. Single-cell analyses revealed preferential enrichment of MES-like and AC/MES-like states in high-risk tumors, accompanied by intensified ligand-receptor interactions with immune and stromal compartments. Despite increased immune infiltration, high-risk tumors displayed features of immune dysfunction and exhaustion. Conclusions: Our study defines a clinically relevant inflammatory cell death signature that integrates tumor cell state plasticity, genomic instability, and immune microenvironment dynamics in glioma. PA.Sig may serve as a prognostic biomarker and provide a rationale for combinatorial strategies targeting cell death pathways and immune modulation.