In 1975, a cytokine was first identified in the serum of mice infected with bacterial endotoxin or previously inoculated with Bacillus Calmette–Guérin (BCG). This cytokine was capable of inducing hemorrhagic necrosis of tumors without damaging normal cells, so it was named tumor necrosis factor (TNF). TNF is primarily produced by activated macrophages, natural killer (NK) cells, and T lymphocytes. The TNF produced by macrophages is designated TNF-α, while the lymphotoxin (LT) produced by T lymphocytes is referred to as TNF-β. Although the sequence homology of TNF-α and TNF-β is low, they bind to the same receptor.

To date, the tumor necrosis factor superfamily (TNFSF) has been found to comprise 19 ligands. These ligands specifically interact with 29 receptors belonging to the tumor necrosis factor receptor superfamily (TNFRSF), forming a complex ligand-receptor signaling system in which each ligand can bind to one or more receptors. Members of these superfamilies initiate a wide range of physiological processes and constitute a critical communication network for regulating the development and homeostasis of the immune system, nervous system, skeletal system, and ectodermal organs.