Influence of STAT1 phosphorylation at Ser727 position on CD8+T cell infiltration in central nervous system malignancies

Phosphorylation of the STAT1 protein at serine 727 position (pSTAT1_S727) is a key posttranslational modification. Its function in the anti-tumor immune response within malignant central nervous system (CNS) tumors remains poorly understood. This study aimed to determine the role of pSTAT1_S727 for anticancer immune modulation in glioblastoma, the most aggressive brain tumor. Our results have shown that STAT1_S727 phosphorylation is closely associated with activation of the anti-tumor immune system. A positive correlation was found between pSTAT1_S727 levels and expression of genes encoding components of the major histocompatibility complex class I ( MHC-I ), as well as other genes involved in tumor antigen presentation. This finding indicates that pSTAT1_S727 plays an important role in enhancing the antigen-presenting capacity of glioblastoma cells, a critical step for tumor recognition by the immune system. Furthermore, high levels of pSTAT1_S727 did significantly correlate with increased intensity of tumor infiltration by cytotoxic CD8 + T cells. These observations were consistently confirmed both by the results from glioblastoma patients, and in experimental murine models, tgus underscoring the significance of this relationship. Hence, the STAT1_ S727 phosphorylation has been considered an important molecular factor promoting the initiation of immune recognition of glioblastoma by enhancing antigen presentation and recruiting effector T cells. However, despite this pro-inflammatory role, the clinical follow-up of patients did not reveal an association between high pSTAT1_S727 levels and improved overall survival. This lack of clinical benefit may be explained by the highly immunosuppressive microenvironment of glioblastoma, with functional exhaustion of infiltrating T cells, thus facilitating the tumor evasion effects. Therefore, activation of the pSTAT1_S727 signaling pathway is necessary for initiating an immune response. However, its action is insufficient to overcome immunosuppression and achieve a significant therapeutic effect. The obtained data highlight the need for combined strategies that enhance the initiation of immune response (e.g., through STAT1 activation), along with blocking the mechanisms of T cell exhaustion within the tumor microenvironment.