Tumor necrosis factor signaling pathway (the central molecular targets are Tumor necrosis factor receptor 1 and Tumor necrosis factor receptor 2) (TNF pathway)

The TNF pathway is a critical signaling cascade activated by the cytokine Tumor necrosis factor (TNF), which binds to two primary receptors, TNFR1 and TNFR2. TNFR1 is constitutively expressed on most cell types and contains a death domain that can activate apoptosis or necrosis, or stimulate inflammatory and pro-survival gene expression through NF-κB and MAPK signaling. TNFR2 is mostly expressed in immune and endothelial cells, lacks a death domain, and instead promotes cell survival and proliferation via TRAF adaptor recruitment. The balance between TNFR1-mediated cell death and survival signaling determines immune outcomes and inflammatory pathology. Therapeutics targeting the TNF pathway—mainly those blocking TNF itself—have revolutionized the treatment of several inflammatory and autoimmune diseases, but carry safety concerns relating to immunosuppression and infection risk.

Other names

TNF signalingTNF-α pathwayTumor necrosis factor signalingTNFR signalingTNF superfamily pathway

Neutralization of TNF ligand (monoclonal antibodies, receptor decoys); Inhibition of TNFR1 or TNFR2 signaling (small molecules, peptides, antibodies); Blockade of downstream signaling pathways (NF-κB, MAPK inhibition)