Carcinoma-derived factors activate myeloid cells via TLR2 to promote metastasis. This study shows that Lewis lung carcinoma (LLC) cells secrete factors that activate macrophages through TLR2 and TLR6, leading to increased production of TNF-α and IL-6, which enhance metastatic growth. Versican, an extracellular matrix proteoglycan upregulated in many tumors, was identified as a key factor in this process. It activates TLR2 and its co-receptors TLR6 and CD14, inducing TNF-α secretion by myeloid cells and promoting metastasis. TLR2 signaling is essential for LLC metastasis, as TLR2-deficient mice showed reduced metastatic growth and improved survival. Versican's pro-inflammatory effects are mediated through TLR2, and its silencing significantly reduces tumor multiplicity and metastatic spread. These findings highlight the role of TLR2 in cancer progression and suggest that targeting TLR2 or its downstream pathways could be a potential strategy for anti-metastatic therapy. The study also demonstrates that versican enhances tumor cell migration, growth, and angiogenesis, which are critical for metastasis. The results indicate that cancer cells exploit the host's innate immune system to create an inflammatory environment conducive to metastatic growth.Carcinoma-derived factors activate myeloid cells via TLR2 to promote metastasis. This study shows that Lewis lung carcinoma (LLC) cells secrete factors that activate macrophages through TLR2 and TLR6, leading to increased production of TNF-α and IL-6, which enhance metastatic growth. Versican, an extracellular matrix proteoglycan upregulated in many tumors, was identified as a key factor in this process. It activates TLR2 and its co-receptors TLR6 and CD14, inducing TNF-α secretion by myeloid cells and promoting metastasis. TLR2 signaling is essential for LLC metastasis, as TLR2-deficient mice showed reduced metastatic growth and improved survival. Versican's pro-inflammatory effects are mediated through TLR2, and its silencing significantly reduces tumor multiplicity and metastatic spread. These findings highlight the role of TLR2 in cancer progression and suggest that targeting TLR2 or its downstream pathways could be a potential strategy for anti-metastatic therapy. The study also demonstrates that versican enhances tumor cell migration, growth, and angiogenesis, which are critical for metastasis. The results indicate that cancer cells exploit the host's innate immune system to create an inflammatory environment conducive to metastatic growth.