Toll-like receptors and toll-like receptor-targeted immunotherapy against glioma

Glioma represents a fast proliferating and highly invasive brain tumor which is resistant to current therapies and invariably recurs. Despite some advancements in anti-glioma therapies, patients' prognosis remains poor. Toll-like receptors (TLRs) act as the first line of defense in the immune system being the detectors of those associated with bacteria, viruses, and danger signals. In the glioma microenvironment, TLRs are expressed on both immune and tumor cells, playing dual roles eliciting antitumoral (innate and adaptive immunity) and protumoral (cell proliferation, migration, invasion, and glioma stem cell maintenance) responses. Up to date, several TLR-targeting therapies have been developed aiming at glioma bulk and stem cells, infiltrating immune cells, the immune checkpoint axis, among others. While some TLR agonists exhibited survival benefit in clinical trials, it attracts more attention when they are involved in combinatorial treatment with radiation, chemotherapy, immune vaccination, and immune checkpoint inhibition in glioma treatment. TLR agonists can be used as immune modulators to enhance the efficacy of other treatment, to avoid dose accumulation, and what brings more interests is that they can potentiate immune checkpoint delayed resistance to PD-1/PD-L1 blockade by upregulating PD-1/PD-L1 overexpression, thus unleash powerful antitumor responses when combined with immune checkpoint inhibitors. Herein, we focus on recent developments and clinical trials exploring TLR-based treatment to provide a picture of the relationship between TLR and glioma and their implications for immunotherapy.