In initial phases of cancer formation, Foxo3 regulation in pDCs and DCs depends on binding of the costimulatory molecules CD80 and CD86 by their ligands. CTLA-4 induces nuclear localization of Foxo3 and de novo transcription of the enzymes IDO, SOD, and catalase. Foxo3 nuclear export and subsequent degradation is stimulated by the binding of CD28, activation of p38 MAPK, and IL-6 production. A mini-circuit of negative cross-regulation is indicated, since IDO negatively regulates IL-6 production by depletion of l-tryptophan, activation of GCN2, and induction of the inhibitory isoform of C/EBPβ. Through Jnk activation, environmentally produced ROS can also cause nuclear retention and activation of Foxo3. IL-6 is initially beneficial for the proliferation of tumor-specific CD8⁺ T lymphocytes; however, increased levels of IL-6 within tumor activate, via C/EBPβ, the transcription of ARG1, NOS2, and NADPH oxidase in MDSCs and TAMs, leading to enhanced generation of ROS and RNS. An additive and possibly synergistic enhancement of this circuit comes from the activity of HIF-1α in hypoxic areas of the tumor. RNS can turn off the immunosuppressive activity in pDCs and DCs by nitrating IDO but also directly inhibit CD4⁺ and CD8⁺ T lymphocytes, assuring the persistence of the negative influence on tumor-specific T cells.