CTLA4 and cancer: Hypoxia and the induction of HIF within the tumor microenvironment has been demonstrated to promote cancer progression, metastasis, and therapy resistance by (i) reducing anti-tumor effector immune cells such as cytotoxic T cells, nature killer cells, and cytokines and/or (ii) increasing immunosuppressive cells such as Tregs and tumor-associated macrophages owing a M2 macrophage phenotype, the expression of immunosuppressive cytokines and inhibitory immune checkpoint molecules such as programmed death 1 (PD-1) receptor or Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) [282].