Thus, CD40L:CD28 CSPs can be triggered in the TME and should, thereby, activate the co-stimulation in CD40L:CD28-engineered T cells while additionally supporting the antitumor response indirectly by inducing tumor cell apoptosis (43, 44), and counteracting various suppressive mechanisms of tumor-stroma components, including immune stimulatory polarization of DCs and tumor-associated macrophages (45–48), counteracting T regulatory cells (49), and modulating the tumor endothelium for improved T cell infiltration (40, 42) (Figure 1). The gene discussed is CD40LG; the disease is neoplasm.