Metabolic, infectious and tumor cell-intrinsic noxae can all evoke the endoplasmic reticulum (ER) stress response in tumor cells, which is critical for tumor cell growth and cancer progression. Evidence exists that the ER stress response can drive a pro-inflammatory program in tumor cells and macrophages, but, to our knowledge, no one has suggested a role for the tumor ER stress response in influencing macrophages and inflammation in the tumor microenvironment. Here we show that macrophages cultured in conditioned medium from ER stressed tumor cells become activated, themselves undergo ER stress with the upregulation of Grp78, Gadd34, Chop and Xbp-1 splicing, suggesting a general activation of the ER stress signaling pathways. Furthermore, they recapitulate, amplify and expand the pro-inflammatory response of tumor cells. We term this phenomenon "transmissible" ER stress. While neither Toll-Like Receptor (TLR)2 nor interleukin 6 receptor (IL6R) signaling is involved, we noticed a reduction in the transmission of ER stress to TLR4 KO macrophages consistent with the fact that a second signal through TLR4 combined with exposure to tumor ER stress conditioned medium results in a faster ER stress response and an enhancement of pro-inflammatory cytokine production in macrophages. The injection of tumor ER stress conditioned medium into wild-type mice elicited a generalized ER stress response in the liver. We suggest that "transmissible" ER stress is a mechanism through which tumor cells can control myeloid cells by directing them towards a pro-inflammatory phenotype, thus facilitating tumor progression
