After circumventing cell-intrinsic mechanisms of apoptosis, tumor cells are subject to elimination pressures by the immune system. Tumor cell-specific antigens play a role during this process, which are recognized by cytotoxic immune cells, leading to their destruction. Fibroblasts and macrophages within the TME also contribute to a growth-suppressive state; however, these cells may later become educated by the tumor to acquire pro-tumorigenic functions. For instance, tumor-associated macrophages (TAMs) support diverse phenotypes within the primary tumor including growth, angiogenesis and invasion by secreting a plethora of pro-tumorigenic proteases, cytokines and growth factors (e.g. EGF, which participates in a paracrine signaling loop via tumor-secreted CSF-1). As tumors grow, immune-suppressor cells, including myeloid-derived suppressor cells (MDSCs) and Treg cells are mobilized into circulation in response to activated cytokine axes induced by tumorigenesis (e.g. TGF-β, CXCL5-CXCR2). MDSCs and Treg cells infiltrate the growing tumor to disrupt immune surveillance via multiple mechanisms, including, but not limited to, disruption of antigen presentation by DCs, inhibition of T and B cell proliferation and activation, or inhibition of NK cytotoxicity. Cancer-associated fibroblasts (CAFs), which become activated by tumor-derived factors (e.g. TGF-β, FGF, PDGF, etc), secrete ECM proteins and basement membrane components, regulate differentiation, modulate immune responses, and contribute to deregulated homeostasis. CAFs are also a key source of VEGF, which supports angiogenesis during tumor growth. In addition to cellular contributions, several extracellular properties contribute to tumor progression, including low oxygen tension, high interstitial fluid pressure, and changes in specific components of the ECM.