Role of the TLR signaling pathway in the pathogenesis of glioblastoma multiforme with an emphasis on immunotherapy

The most malignant brain tumor, glioblastoma multiforme (GBM), has a high mortality rate. Recently, translational elements in GBM therapy have emerged as novel therapeutic strategies in addition to conventional treatment methods. In this way, Toll-like receptor (TLR), PI3K/Akt/mTOR, MAPK/ERK, NOTCH, and other signaling pathways have recently become some of the main signaling pathways in brain tumors. The immunological reactions to brain tumors are mediated by these mechanisms. A family of proteins known as TLRs is essential to the natural defense mechanism because it can identify and react to infections and other danger signals. TLRs have dual functions in the glioma microenvironment including that they can initially activate the innate and adaptive immune responses that support antitumor activity and secondly, their activation can also contribute to tumor progression by promoting inflammation and immune evasion, as they are expressed on both immune cells and tumor cells. TLR agonists are receiving more attention in the treatment of glioma because some of them have demonstrated survival benefits in clinical studies when used in conjunction with immunotherapy, chemotherapy, radiation therapy, and immune checkpoint inhibitors. The most exciting use of TLR agonists is that they can be used as immunomodulators to avoid dose accumulation, boost the efficiency of other therapies, and, by upregulating PD-1, reinforce delayed immune checkpoint resistance against PD-1/PD-L1 inhibition. Therefore, the use of TLR agonists can lead to PD-L1 overexpression, which in turn enhances the efficacy of checkpoint inhibitors and triggers potent anticancer immune responses. In this article, we describe the function of the TLR signaling system, the cellular and molecular elements contributing to the etiology of glioblastoma multiforme, the connection between TLRs and glioma, and their significance for immunotherapy.