Multiomics Investigation of Exhausted T Cells in Glioblastoma Tumor Microenvironment: CCL5 as a Prognostic and Therapeutic Target

Glioblastoma multiforme (GBM) is a common malignancy with poor prognosis, and exhausted T (TEX) cells, a subset of T cells characterized by progressive loss of effector functions, play a critical role in its progression. This study aimed to investigate the impact of TEX-related genes on immune function, prognosis, and drug sensitivity in GBM through multiomics analysis. Initially, we identified a novel set of TEX-related genes specific to GBM and screened hub genes (<i>CCL5</i>, <i>IL18</i>, <i>CXCR6</i>, <i>FCER1G</i>, <i>TNFSF13B</i>) using conventional statistical methods combined with machine learning. A prognostic risk model was subsequently constructed based on TCGA data and validated in the CGGA cohort. Single-cell and pharmacogenomic analyses revealed significant differences in tumor microenvironment composition and drug sensitivity between risk groups. Notably, Palbociclib emerged as a potential therapeutic agent targeting the novel discovered biomarker <i>CCL5</i>. RT-qPCR results showed that T cells with low <i>CCL5</i> expression exhibited reduced expression of immune checkpoint-related genes (<i>PD1</i>, <i>TIM3</i>, <i>LAG3</i>) and increased expression of <i>CD28</i>, suggesting enhanced immune function. In conclusion, our findings highlight five hub genes as prognostic markers that could stratify GBM patients with different immune landscapes and levels of drug sensitivity. Furthermore, experimental results suggest that low <i>CCL5</i> expression could alleviate T cell exhaustion and represent a promising therapeutic target, offering new strategies for improving GBM prognosis.