The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy.

Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans. The application of natural cytokines in clinical studies has not been clearly established, and there are often problems associated with toxicity or lack of efficacy. The key reasons can be attributed to the pleiotropy of cytokine receptors and undesired activation of off-target cells. With a deeper understanding of the structural principles and functional signals of cytokine-receptor interactions, artificial modification of cytokine signaling through protein engineering and synthetic immunology has become an increasingly feasible and powerful approach. Engineered cytokines are designed to selectively target cells. Herein, the theoretical and experimental evidence of cytokine engineering is reviewed, and the "supercytokines" resulting from structural enhancement and the "immunocytokines" generated by antibody fusion are described. Finally, the "engager cytokines" formed by the crosslinking of cytokines and bispecific immune engagers and other synthetic cytokines formed by nonnatural analogs are also discussed.