Figure 1.

Toll-Like Receptors (TLRs) signaling pathways, intra-, and inter-signaling crosstalk circuits, and their regulatory loops. Cell surface expressed TLRs, including TLR1, 2, 4, 5, 6, 10, and 11, and intracellularly expressed TLRs on endosomal membranes, including TLR3, 7, 8, and 9, recognize their specific pathogen-associated molecular patterns (PAMPs) to activate their signaling pathways. Small molecules and/or microbial ligands, depicted on the top of the cell surface expressed TLRs, occupy the extracellular domain of the TLRs. Upon activation, they induce conformational changes in the intracellular domain to induce a signaling pathway by recruitment of the adaptor molecules (i,e., MyD88, TIRAP, TRIF, and TRAM) followed by downstream signals leading to the activation of sevral transcriptions factors (i.e., AP-1, NF-κB, IRF-3 or IRF-7). These key transcription factors drive the expression of several proinflammatory cytokines as well as antiapoptotic factors. Pro-inflammatory cytokines can promote cancer progression in three ways; firstly through facilitating immortalization by activating the proapoptotic factors, secondly recruiting the immune cells for creating a tumor-friendly microenvironment, and lastly by expanding the blood vessel to maximize the chances of metastasis (52–55). The image has been created with Biorender.com (56).