TGFB1 and neoplasm: Tumor-extrinsic resistance can arise via an immunosuppressive TME with (i) physical barriers, e.g., a dense extracellular matrix or abnormal vasculature causing exclusion of infiltrating immune cells from the tumor; (ii) accumulation of immunosuppressive cell population, e.g., Tregs, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs); (iii) high levels of immunosuppressive cytokines, such as TGF-β and IL-10; and (iv) metabolic reprogramming of tumors to adapt to nutrient deprivation and hypoxia, which inhibit T cell function.