TGFβ is a multifunctional cytokine implicated in many cellular processes in both developing and adult organisms. Its signaling role TGFβ in cancer is quite complex, with evidence for both early suppression (by inhibition of cell growth and apoptosis) and later enhancement of tumor formation. Tumor promotion likely reflects the outcome of at least two different mechanisms. The one occurring through promotion of epithelial mesenchymal transition (EMT), leads to enhanced migration, invasion, infiltration, and extravasation of the tumor cells, while at least one of the others reflects action of a paracrine signaling pathway whereby TGFβ in the TME activates cancer-associated fibroblasts (CAF), promotes angiogenesis and may even inhibit anti-tumor immune responses causing promotion of tumor metastasis. Such effects may help explain the recent evidence for a role for tissue resident macrophages in promotion of metastatic spread of ovarian cancer cells, and their adoption of a cancer stem cell phenotype. TGFβ modulates activation/differentiation of multiple cell targets, including fibroblasts, mesenchymal stem cells, epithelial tumor cells, adipose tissue-derived stem cells, and endothelial cells and can also promote angiogenesis and migration in the TME, and modulate acquired immunity. Thus TGFβ inhibits T cell activation, proliferation, differentiation, and migration of (CD8+ ) effector T cells (inhibition of IFNα and IL-2, and enhanced expression of PD-1), and both inhibits the differentiation of CD4+ T cells into various effector subtypes, and also promotes development of regulatory (immunosuppressive) CD4+ T cells [28-32]. Using a gene screening technique to assess correlation between gene expression frequencies and prognosis in human head and neck squamous cell carcinoma, CCR4 and CCR8 (chemokine receptor genes) and P2RY14 (involved in the G-protein pathway and regulation of the immune stem cell compartment) were identified as key genes important in the promotion of development of a TME which could stimulate anti-tumor immunity and inhibit tumor growth and invasion.