Toll-Like Receptors (TLRs) in the Tumor Microenvironment (TME): A Dragon-Like Weapon in a Non-fantasy Game of Thrones.

Toll-like receptors (TLRs) in the tumor microenvironment (TME) are expressed not only in innate and adaptive immune cells but also in stromal cells such as fibroblasts, endothelial cells (EC), and tumor cells. The role of TLR signaling in the TME is complex and controversial due to their wide expression within the TME. Moreover, TLR signaling may culminate in different outcomes depending on the type of tumor, the implicated TLR, the type of TLR ligands, and, most importantly, the main type of cell(s) that are targeted by TLR ligands. Understanding to what extent these complex TLR signals impact on tumor progression merits further investigation, as it can help improve existing anti-cancer treatments or unravel new ones. In most cases, TLR signaling in tumor cells and in immune cells is associated with pro-tumoral and anti-tumoral effects, respectively. A better understanding of the relationship between TLRs and the TME, especially in humans, is required to design better anti-cancer therapies, considering that most current TLR-involved treatments were disappointing in clinical trials.In this chapter, we will discuss the impact of TLR signaling on the hallmarks of cancer, by highlighting their effects in tumor, immune, and stromal cells within the TME. Furthermore, we will discuss how the understanding of the role of TLRs can pave the way to develop new anti-cancer treatments and even predict clinical outcome and chemotherapy efficacy.