Ruxolitinib suppresses tumor growth in PTEN-deficient glioblastoma by inhibiting the STAT3-PDL1 axis-mediated the M2 polarization of macrophages.

BACKGROUND

Glioblastoma (GBM) is the most malignant form of brain tumor, and GBM patients with poorer prognosis and highly immunosuppressive tumor microenvironment (TME) often exhibit PTEN deficiency in their tumor tissues. Therefore, new therapeutic strategies targeting immunosuppressive TME maybe useful in PTEN-deficient GBM.

METHODS

Bioinformatics was used to assess gene expression, survival time and immunoinfiltration in PTEN-deficient GBM. CRISPR-Cas9 was used to construct gene knockout cell lines. C57BL/6 mouse orthotopic GBM models were used to conduct survival analysis and evaluate treatment effect of Ruxolitinib. Flow cytometry, immunohistochemistry, immunofluorescence and quantitative real-time PCR (qRT-PCR) to detect the polarization of macrophages. Immunoblotting, immunohistochemistry, qRT-PCR, enzyme linked immunosorbent assay, and dual-luciferase reporter assay were used to conduct mechanism research.

RESULTS

We identified that the elevated levels of phosphorylated STAT3 (p-STAT3) in PTEN-deficient GBM facilitate PDL1 transcription, which subsequently drives M2 polarization of macrophages. Furthermore, PTEN deficiency, along with high expression levels of STAT3 and PDL1, are associated with a shorter survival time in GBM patients. Notably, in orthotopic mouse models of GBM with PTEN deficiency, Ruxolitinib therapy reduces the levels of p-STAT3 and PDL1, inhibits the infiltration of M2 macrophages, and suppresses tumor growth.

CONCLUSIONS

The STAT3-PDL1 axis plays a crucial role in the M2 polarization of macrophages in PTEN-deficient GBM. The blockade of the STAT3-PDL1 axis by Ruxolitinib regulates the anti-tumor immune response and curtails tumor progression in PTEN-deficient GBM, highlighting its significant clinical implications.