Tumor necrosis factor receptor superfamily member 1A and Tumor necrosis factor receptor superfamily member 1B (TNFR1 and TNFR2)

Tumor necrosis factor receptors 1 (TNFR1) and 2 (TNFR2) are the primary mediators of the biological effects of tumor necrosis factor (TNF), a key cytokine in systemic inflammation and immune regulation [1, 14]. TNFR1 is ubiquitously expressed and contains an intracellular death domain that can trigger either pro-inflammatory gene expression via NF-kappaB or programmed cell death through apoptosis and necroptosis [4, 10]. TNFR2 has a more restricted expression pattern, primarily on immune cells, endothelial cells, and neurons, and lacks a death domain, instead promoting cell survival, proliferation, and tissue repair [7, 15]. Dysregulation of the TNF-TNFR axis is central to the pathogenesis of numerous autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, as well as cancer and chronic kidney disease [5, 11, 16]. While traditional therapies like Etanercept and Infliximab broadly inhibit TNF activity, emerging therapeutic strategies focus on selective modulation—such as TNFR1 antagonism to reduce inflammation or TNFR2 agonism/antagonism for immune modulation—to improve efficacy and safety profiles [3, 6, 12].

Other names

TNFRSF1ATNFRSF1BCD120aCD120bp55p75TNF-R1TNF-R2Tumor necrosis factor receptor 1Tumor necrosis factor receptor 2p60p80

Drugs targeting these receptors primarily function by neutralizing the ligand (TNF-alpha) to prevent receptor activation, or by directly binding to the receptors as antagonists or agonists. TNF-alpha blockers like Etanercept and Infliximab prevent both TNFR1 and TNFR2 signaling. Selective TNFR1 antagonists aim to block pro-inflammatory and apoptotic pathways while sparing TNFR2-mediated survival signals. TNFR2-targeted therapies include antagonists to deplete regulatory T cells in cancer and agonists to expand them in autoimmune conditions.