STING activation increases the efficiency of temozolomide in PTEN harbouring glioblastoma cells

Glioblastoma is one of the most aggressive tumours, resistant to all applied therapy regiments and prone to relapse. Median survival rates are therefore only expressed as months. STING agonists are immunomodulatory molecules that activate type I interferon expression, making them potentially useful in regulating the tumour microenvironment. Since PTEN serves as a critical phosphatase in activating interferon-regulating transcription factors and is frequently mutated in glioblastoma cells, this study aimed to investigate STING activation in glioblastoma cell lines, examining whether they harbour the PTEN protein or not.°.

T98G and U118MG glioblastoma cell lines were treated with the 2'3'-c-di-AM(PS)2(Rp,Rp) STING agonist together with or without the chemotherapeutic agent temozolomide. cGAS/STING pathway components were subsequently analysed using qRT-PCR, western blot, and ELISA methods.

Our results showed that PTEN-harbouring T98G cells responded well to STING activation, leading to increased temozolomide efficacy. In contrast, STING activation in U118MG cells did not affect the response to temozolomide. mRNA expression levels of STING, IRF3, NF-KB, and RELA genes were significantly increased at the combined treatment groups in T98G cell line. Conversely, combined treatment with STING agonist and temozolomide did not affect mRNA expression levels of cGAS/STING pathway genes in U118MG cells.

Our data offers new evidence suggesting that STING agonists can effectively be used to increase temozolomide response in the presence of PTEN protein. Therefore, increased GBM therapy success rates can be achieved by employing the PTEN expression status as a predictive biomarker before treating patients with a chemotherapeutic agent in combination with STING agonist.