The antitumor activity of TNF receptor (TNFR)-based therapy is executed through activation signals (upper half) to effector and memory T cells, which create an initial wave of tumor killing mediated by CD8⁺ cytolytic T cells and the indirect tumoricidal activity of IFN-γ [147]. Antitumor immunity can also be enhanced at this stage by the abrogation of regulatory T cell (Treg) function. Priming signals (lower half) to naive T cells in the tumor-draining lymph node also contribute to the TNFR-mediated response by generating secondary, delayed waves of tumor-specific effector cells. CD4⁺ Th1 cells and NK and NKT cells play essential roles in both stages, via IFN-γ-dependent CD8⁺ T cell ‘help’ in the effector phase (upper half) or by ‘licensing’ dendritic cell-mediated priming of naive T cells (lower half). The central box represents a source of exogenously administered agonist reagents, as would be applied therapeutically. The impact of costimulatory molecules expressed naturally by host DC is purposely discounted in the current figure. Dominant routes of TNFR-dependent immunomodulation are indicated in bold; secondary actions are italicized. GITR: Glucocorticoid-induced TNF receptor; NK: Natural killer.