Basic understanding and therapeutic approaches to target toll‐like receptors in cancerous microenvironment and metastasis

Abstract

Toll-like receptors (TLRs) are transmembrane components that sense danger signals, like damage- and pathogen-associated molecular pattern molecules, as receptors, and maintain homeostasis in tissues. They are mainly involved in immune system activation through a variety of mediators, which either carry out (1) elimination of pathogenic threats and redressing homeostatic imbalances or (2) contribution to the initiation and worsening of pathological conditions, including cancers. Under physiological conditions, TLRs coordinate the innate and adaptive immunity, and inhibit autoimmune disorders. In pathological conditions, such as cancer, they can present both tumor and receptor-specific roles. Although the roles of individual TLRs in various cancers have been described, the effects of targeting TLRs to treat cancer and prevent metastasis are still controversial. A growing body of literature has suggested contribution of both activators and inhibitors of TLR signaling pathway for cancer treatment, dependent on several context-specific factors. In short, TLRs can play dual roles with contradictory outcomes in neoplastic conditions. This hampers the development of TLR-based therapeutic interventions. A better understanding of the interwoven TLR pathways in cancerous microenvironment is necessary to design TLR-based therapies. In this review, we consider the molecular mechanisms of TLRs signaling and their involvement in tumor progression. Therapeutic modalities targeting TLRs for cancer treatment are discussed as well.

Targeting Multiple Receptors to Increase Checkpoint Blockade Efficacy

“…Toll-like receptors (TLRs) are found on dendritic cells, NK cells, and macrophages and activation of TLRs leads to the production of factors that stimulate inflammatory and pro-immunity pathways. Agonists of TLRs have previously been investigated for their anti-cancer properties; however their complex role in both pro- and anti-tumor signaling has complicated their therapeutic development [66]. Nevertheless, immunostimulating TLR9 agonists are in various phases of clinical trial in combination with PD-1 inhibitors (NCT03618641, NCT03326752, and NCT03445533).…”

Prognostic Significance of Regional/Systemic Metabolic Parameters on 18F-FDG PET in Pulmonary Lymphoepithelioma-Like Carcinoma

“…One possible explanation for the discrepancy of the impact on survival could be the difference in chemosensitivity between TRLN and other lesions. Numerous basic studies have revealed diverse gene expression patterns of the different lesions and observed that lymph-node metastasis was often biologically less malignant (26)(27)(28). Primary and distant metastatic lesions were more heterogeneous in cell clonality and tumor microenvironment, which contribute to more tough characteristics in drug delivery, hypoxia, and immune escape, thus more resistant to chemotherapy (29,30).…”

Activation of Toll-like receptor 2 via specific agonists promotes OXPHOS and glycolysis in gastric cancer cells rather than other Toll-like receptors

“…Thus, TLR9 requires stimulants such as microbial DNA to translocate into endosome to trigger the action 21 , which is quite different from TLR4. Besides, both of TLR4 and TLR9 can trigger MyD88-dependent pathway but TLR4 can also trigger MyD88-independent one, which is through TIR-domain-containing adapter-inducing interferon-β (TRIF), resulting in interferon regulatory factor (IRF) activation and anti-viral responses 22 . This indicates that TLRs may differ in downstream modulators and thus express diverse biological characteristics.…”