HSP72 is a stimulus for activating toll-like receptor 2 in M2 macrophages leading to IL-6-mediated tumor malignancy

Background: M2-polarized macrophages aggressively modulate the tumor microenvironment and enhance tumor cell malignancy. As intracellular molecules are released by damaged or stressed cells, damage-associated molecular patterns (DAMPs) bind to toll-like receptors (TLRs) on cells in the tumor microenvironment, inducing inflammation and epithelial-mesenchymal transition. However, recent studies on the crosstalk between DAMPs and M2-polarized macrophages (M2 macrophages) during tumor progression have not provided conclusive results. Objective: We investigated the role of toll-like receptors (TLRs) in IL-6 production by M2 macrophages and searched for cancer cell-derived DAMPs that can activate the TLRs responsible for IL-6 production. Results: TLR2 activation was required for IL-6 production by M2 macrophages. The malignancy of cancer cells was increased by the activation of this pathway. Cancer-derived HSP 72 acted as a ligand that stimulates the TLR2 signaling pathway in M2 macrophages, triggering IL-6 production. Conclusion: TLR 2 stimulation in M2 macrophages enhances tumor malignancy by upregulating IL-6. Heat shock protein 72 (HSP72) is a potent TLR2 stimulator. Our findings reveal a connection between TLR2 and M2-polarized macrophages in tumor malignancy and may be useful for developing effective treatments for tumor relapse.