PHF23-Related Prognostic Signature Modulates Immune Microenvironment and Promotes Tumor Malignancy in Glioma.

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Gliomas present significant molecular and immunological challenges, necessitating novel biomarkers and therapeutic strategies.
• PHD finger protein 23 (PHF23) is implicated in cancer, but its specific role in glioma pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the pathological role of PHF23 in glioma progression.
• To develop a PHF23-based prognostic signature for glioma risk stratification.
• To identify potential therapeutic targets for high-risk glioma subtypes.

Main Methods:

• Utilized Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets.
• Applied machine learning to construct a PHF23-related prognostic signature (PHF23-RPS).
• Performed pharmacogenomic screening, molecular dynamics simulations, and in vitro/in vivo functional assays.

Main Results:

• PHF23 was significantly upregulated in high-grade gliomas.
• The PHF23-RPS demonstrated strong predictive performance (AUC = 0.853).
• Identified an "inflamed yet immunosuppressive" subtype with a TMB paradox, characterized by M2 macrophages and immune exhaustion.
• Entospletinib emerged as a potential therapeutic agent with stable binding affinity (-7.7 kcal/mol).
• PHF23 silencing inhibited glioma malignancy in preclinical models.

Conclusions:

• PHF23 is a critical oncogenic driver in glioma, and the PHF23-RPS is valuable for risk stratification.
• Entospletinib represents a promising immunomodulatory therapeutic option for high-risk gliomas with specific immune profiles.