Multiple immune inhibitory and co-stimulatory pathways in the tumor microenvironment are targets of therapeutic manipulation by antibodies or drugs. Cells in the tumor microenvironment express multiple inhibitory cytokines, ligands, and cognate receptors (red) that down-modulate the antitumor activity of immune effector cells including cytotoxic T lymphocytes (CTL). Some of these inhibitory proteins are expressed by tumor cells themselves and others are expressed by tumor-infiltrating suppressive cells including T reg cells and myeloid derived suppressor cells (MDSCs). T reg cells inhibit antitumor CTL activity by producing soluble factors such as IL-10 and TGF-β, whereas MDSCs inhibit immunity through metabolic enzymes such as IDO and arginase. These inhibitory signals are counterbalanced by signals that enhance immune activation (green), a number of which are transduced by members of the TNFR family (CD40, CD137, OX40, and CD27). Blocking antibodies or drugs are in development or clinical testing for each of the inhibitory molecules depicted in the figure, and agonist antibodies are in development or clinical testing for each of the activating TNFR family members depicted (Table 1). DC/Mφ, DCs/macrophages.