Numerous studies demonstrate that HMGB1, upon release from stressed or dying tumor cells, engages RAGE, TLR4, or TNFR1 to initiate canonical NF-κB activation, resulting in phosphorylation of IKKα/β, degradation of IκBα, and nuclear translocation of p65 [92,204,205]. This evidence concerns the gene TLR4 and neoplasm.