CTLA4 and cancer: However, the formation of tumor immunosuppressive microenvironment limits the further clinical application of immunotherapy, which is manifested at the cellular level by tumor infiltration of Treg (regulatory T cells), TAM (tumor-associated macrophages), and MDSC (myeloid-derived suppressor cells), and at the metabolic level by hypoxia, adenosine accumulation and immunosuppressive cytokine secretion, accompanied by upregulation of PD-1 or CTLA-4 expression on the T cell surface and PD-L1 expression on cell membranes of DCs or cancer cells (Rabinovich et al., 2007).