HK3 stimulates immune cell infiltration to promote glioma deterioration

Glioma is the most common and lethal type of brain tumor, and it is characterized by unfavorable prognosis and high recurrence rates. The reprogramming of energy metabolism and an immunosuppressive tumor microenvironment (TME) are two hallmarks of tumors. Complex and dynamic interactions between neoplastic cells and the surrounding microenvironment can generate an immunosuppressive TME, which can accelerate the malignant progression of glioma. Therefore, it is crucial to explore associations between energy metabolism and the immunosuppressive TME and to identify new biomarkers for glioma prognosis.

In our work, we analyzed the co-expression relationship between glycolytic genes and immune checkpoints based on the transcriptomic data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) and found the correlation between HK3 expression and glioma tumor immune status. To investigate the biological role of HK3 in glioma, we performed bioinformatics analysis and established a mouse glioblastoma (GBM) xenograft model.

Our study showed that HK3 significantly stimulated immune cell infiltration into the glioma TME. Tissue samples with higher HK3 expressive level showed increasing levels of immune cells infiltration, including M2 macrophages, neutrophils, and various subtypes of activated memory CD4⁺ T cells. Furthermore, HK3 expression was significantly increasing along with the elevated tumor grade, had a higher level in the mesenchymal subtype compared with those in other subtypes of GBM and could independently predict poor outcomes of GBM patients.

The present work mainly concentrated on the biological role of HK3 in glioma and offered a novel insight of HK3 regulating the activation of immune cells in the glioma microenvironment. These findings could provide a new theoretical evidence for understanding the metabolic molecular within the glioma microenvironment and identifying new therapeutic targets.