The study investigates how metastatic carcinomas activate myeloid cells to promote metastasis. Lewis lung carcinoma (LLC) was found to be the most potent activator of macrophages, leading to the production of IL-6 and TNF-α through the activation of Toll-like receptors (TLRs) TLR2 and TLR6. Both TNF-α and TLR2 are essential for LLC metastasis. The extracellular matrix proteoglycan versican, which is upregulated in many human tumors, was identified as a macrophage activator that acts via TLR2 and its co-receptors TLR6 and CD14. Versican strongly enhances LLC metastatic growth by activating TLR2:TLR6 complexes and inducing TNF-α secretion by myeloid cells. These findings explain how advanced cancer cells exploit the host's innate immune system to create an inflammatory microenvironment conducive to metastasis. The study also demonstrates that versican secretion by LLC cells is crucial for metastatic spread to the lung, liver, and adrenal gland, and that this process depends on TLR2-mediated myeloid cell activation and TNF-α production. Versican's pro-inflammatory activities rely on TLR2 but not TLR4, and its interaction with TLR2 involves TLR6 as a co-receptor. The study suggests that targeting versican or its interaction with TLR2 could be a potential strategy for anti-metastatic intervention.The study investigates how metastatic carcinomas activate myeloid cells to promote metastasis. Lewis lung carcinoma (LLC) was found to be the most potent activator of macrophages, leading to the production of IL-6 and TNF-α through the activation of Toll-like receptors (TLRs) TLR2 and TLR6. Both TNF-α and TLR2 are essential for LLC metastasis. The extracellular matrix proteoglycan versican, which is upregulated in many human tumors, was identified as a macrophage activator that acts via TLR2 and its co-receptors TLR6 and CD14. Versican strongly enhances LLC metastatic growth by activating TLR2:TLR6 complexes and inducing TNF-α secretion by myeloid cells. These findings explain how advanced cancer cells exploit the host's innate immune system to create an inflammatory microenvironment conducive to metastasis. The study also demonstrates that versican secretion by LLC cells is crucial for metastatic spread to the lung, liver, and adrenal gland, and that this process depends on TLR2-mediated myeloid cell activation and TNF-α production. Versican's pro-inflammatory activities rely on TLR2 but not TLR4, and its interaction with TLR2 involves TLR6 as a co-receptor. The study suggests that targeting versican or its interaction with TLR2 could be a potential strategy for anti-metastatic intervention.