Fig. 3. Cytokine targeting and delivery.

a, Cytokine fusion proteins and their roles in redirecting cytokines to a specific site or cell type. Immunocytokines are cytokines fused to antibodies that target cytokines to distinct locations. This strategy can, for example, be used with the pro-inflammatory cytokine IL-12 to actively target exposed DNA found in necrotic areas within the tumour microenvironment (TME). Tumour localization can be achieved by directing cytokines to the tumour’s extracellular components, such as collagen. Fusing a cytokine to collagen-binding proteins can anchor it in collagen and increase its retention in the tumour. Cytokine prodrugs can be engineered by fusion protein technology. These prodrugs usually exploit tumour-associated proteases that remove the inactivation domain from the cytokines through cleavage to release tumour-specific active cytokines. b, Routing cytokines with nanomedicine. Cytokine receptors are expressed on the cell surface and, thus, nanomedicine strategies must avoid uptake by immune cells. Nanoparticles can be designed with surface-displayed cytokines to target T cells¹³⁹. In another approach, polymeric nanoparticles target collagen in the extracellular matrix, aiming for local sustained release of cytokines. COL-IV, type IV collagen.