Toll-like receptor-guided therapeutic intervention of human cancers: molecular and immunological perspectives

Abstract

Toll-like receptors (TLRs) serve as the body’s first line of defense, recognizing both pathogen-expressed molecules and host-derived molecules released from damaged or dying cells. The wide distribution of different cell types, ranging from epithelial to immune cells, highlights the crucial roles of TLRs in linking innate and adaptive immunity. Upon stimulation, TLRs binding mediates the expression of several adapter proteins and downstream kinases, that lead to the induction of several other signaling molecules such as key pro-inflammatory mediators. Indeed, extraordinary progress in immunobiological research has suggested that TLRs could represent promising targets for the therapeutic intervention of inflammation-associated diseases, autoimmune diseases, microbial infections as well as human cancers. So far, for the prevention and possible treatment of inflammatory diseases, various TLR antagonists/inhibitors have shown to be efficacious at several stages from pre-clinical evaluation to clinical trials. Therefore, the fascinating role of TLRs in modulating the human immune responses at innate as well as adaptive levels directed the scientists to opt for these immune sensor proteins as suitable targets for developing chemotherapeutics and immunotherapeutics against cancer. Hitherto, several TLR-targeting small molecules (e.g., Pam3CSK4, Poly (I:C), Poly (A:U)), chemical compounds, phytocompounds (e.g., Curcumin), peptides, and antibodies have been found to confer protection against several types of cancers. However, administration of inappropriate doses of such TLR-modulating therapeutics or a wrong infusion administration is reported to induce detrimental outcomes. This review summarizes the current findings on the molecular and structural biology of TLRs and gives an overview of the potency and promises of TLR-directed therapeutic strategies against cancers by discussing the findings from established and pipeline discoveries.

PTK2 promotes lung cancer progression via cross-talk regulation between EGFR- and TLR-mediated signaling

“…In this study, we examined functional roles of PTK2 in lung cancer progression via the cross-talk between EGFR-and TLRs-mediated signaling, which has been considered as critical therapeutic targets for the intervention of lung cancer diseases [3][4][5][6][7][8][9]. We found that the survival of NSCLC patients with up-regulated PTK2 was critically lower than that of TLRs-mediated signaling is essentially implicated in lung cancer progression [3][4][5][6][7][8][9][10][11][12], the ability of cancer progression was significantly enhanced in response to EGF, Pam3csk4 (an agonist of TLR1/2), and FSL-1…”

“…With advanced omics data analysis of lung cancer patients, numerous genetic and molecular studies have been reported for pathophysiological characterization of lung cancer progression and the development of target-therapeutics [3][4][5]. Recently, the development of therapeutic targets focusing on toll-like receptors (TLRs) and epidermal growth factor receptor (EGFR) signaling is being potentially considered in lung cancers [6][7][8][9]. TLRs have been identified on tumor cells, where their activation may orchestrate downstream signaling pathways that serve crucial functions in tumorigenesis and tumor progression [6,7,10].…”

“…Recently, the development of therapeutic targets focusing on toll-like receptors (TLRs) and epidermal growth factor receptor (EGFR) signaling is being potentially considered in lung cancers [6][7][8][9]. TLRs have been identified on tumor cells, where their activation may orchestrate downstream signaling pathways that serve crucial functions in tumorigenesis and tumor progression [6,7,10]. In addition, TLRs play an essential role in lung cancer progression including cell growth, invasion, and angiogenesis [10].…”

Polymorphism of IL‐12/IL‐23 axis is associated with coronary heart disease

“…In recent years, accumulating studies indicated inflammation are closely related to the progression of CHD 1,2 . Interleukins (ILs) are inflammatory cytokines involved in pro‐inflammatory and anti‐inflammatory responses through interactions with a variety of receptors, such as Toll‐like receptors (TLRs) 3 . Research has suggested that ILs and TLRs could represent promising targets for the therapeutic intervention of inflammation‐associated diseases 4 .…”

The Virtual Screening of Compounds from the ZINC Database against PARP‐1 in Triple‐Negative Breast Cancer

“…reviewed the TLR proteins and the therapeutic strategies against cancers. [17] A chemical compound that has pharmacological or biological activity that is likely to be therapeutically useful but may still have a sub-optimal structure that needs to be modified to fit better to the target is called a lead compound in the drug discovery process. Lead compounds offer the possibility of being followed by backup compounds.…”