One of the earliest evidence of cell-non-autonomous UPR transmission was described in a study by Mahadevan et al. (46) where the conditioned medium prepared from chemically induced UPR in tumor cells was shown to activate a generalized UPR in macrophages and pro-inflammatory cytokine signaling partly via Toll-like receptor 4 (TLR4) signaling. Here, TLR4 is linked to neoplasm.