TNF and neoplasm: Alternately, engineering CAR T-cells to release pro-inflammatory cytokines IL-12, IL-15, IL-18, or IL-21 (204, 256), or integrating CD28 costimulatory domain into the CAR structure to stimulate the release of IFN-γ, GM-CSF, and TNF have shown promise in the anti-tumor activities of CAR T-cells in the immunosuppressive TME (257, 258).