Besides using nonhuman proteins to eliminate tumors by direct action, malignant cells can also be destroyed by attracting and stimulating immune cells. To activate the immune response, certain cytokines can be administered. Unfortunately, sys­temic administration of cytokines can lead to unwanted side effects, such as fever, inammation or other u-like symptoms [160]. Therefore, a more targeted approach is desirable for patient safety. Furthermore, cytokine targeting can also improve the duration of the cytokine response as the small cytokines are relatively rapidly removed from the body. Overall, immunocytokines can enrich the cytokine in the tumor tissue, decrease systemic distribution and, thus, reduce the side effects. Typically targeting is achieved by fusing the cytokines to full length antibodies, their Fab- or scFv fragments or other afnity binders. The most frequently used cytokine is interleukin 2 (IL-2), a signaling molecule that regulates the activity of lymphocytes. IL-2 triggers the differentiation of T-cells and can induce cell killing through NK-cells and cytotoxic T-cells. As the high potency of wild-type IL-2 often overshadows the afnity of the fused antibody, tumor targeting could be limited. Therefore, IL-2 muteins with reduced binding are becoming the cytokine of choice. For instance, recently an IL-2 with increased CD122 binding and decreased CD25 binding fused to a tumor specic antibody was designed [161]. A monomeric CEA­targeted IL-2 variant cytokine used a similar approach, weakening CD25 binding to avoid T-reg activation while improving binding to the CEA antigen [162]. Currently there are more than ten different IL-2 based immunocytokines in clinical trials, addressing antigens such as GD2, CD20, EDB, Tenascin C, CEA, FAP, EpCAM, or D7 [163]. Although the obvious design would place the antibody at the N-terminus of the fusion protein, while the cytokine is found at the C-terminal end, many other variants have been developed in the last two decades utilizing both ends or a combi­nation between fusion or the heavy or light chain [164]. Overall three effects of immunocytokines have to be orchestrated to obtain a long-lasting cure; rst, immune cells have to inltrate the tumor attracted by chemokine and antibody-mediated targeting; second, these immune cells must be activated, ideally in a co-stimulatory way to generate a memory effect; third, tumor-mediated immune tolerance must be eliminated. All that can be achieved by a careful design of immune modulating fusion proteins [165].