MTP-PE is a specific ligand of NOD~2~, a receptor found primarily on monocytes, dendritic cells and macrophages. MTP-PE is a potent activator of monocytes and macrophages. Activation of human macrophages by MTP-PE is associated with production of cytokines, including tumor necrosis factor (TNF~α~), interleukin-1 (IL-1~β~), IL-6, IL-8, and IL-12 and adhesion molecules, including lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). In vitro-treated human monocytes killed allogeneic and autologous tumor cells (including melanoma, ovarian, colon, and renal carcinoma), but had no toxicity towards normal cells. In vivo administration of MTP-PE resulted in the inhibition of tumor growth in mouse and rat models of lung metastasis, skin and liver cancer, and fibrosarcoma. Significant enhancement of disease-free survival was also demonstrated in the treatment of dog osteosarcoma and hemangiosarcoma with MTP-PE as adjuvant therapy. The exact mechanism by which MTP-PE activation of monocytes and macrophages leads to antitumor activity in animals and humans is not yet known.