Tumor necrosis factor-alpha (TNF-alpha), also known as TNF superfamily member 2 (TNFSF2), mainly produced by monocyte-macrophages, is a multifunctional cytokine that has a recognized immune role in innate and adaptive immunity and the normal physiological function of immune cells and can stimulate the acute phase of the immune response. TNFR 2 is a type I transmembrane glycoprotein consisting of approximately 439 to 461 amino acids (slight differences in amino acid numbers in the literature from different sources, possibly due to small differences in experimental conditions or gene sequences). These amino acids can be roughly divided into three parts: extracellular, transmembrane, and intracellular segment.

The biological activity of TNF-alpha is very complex, including the effects of hematopoiesis, immunity, and regulation on inflammation in blood vessels and coagulation and a variety of organs. It can enhance the effect of cytotoxic T cells, increase the expression of MHC antigen, cause leukocytosis, and enhance the adhesion of endothelial cells; in addition, it can inhibit multiple tumor cells and virus-infected cells. In response to pathogens, TNF-alpha is one of the first substances to be released and can function in many organs. TNF-alpha stimulates the release of hypothalamic releasing hormone from the adrenal cortex, suppresses appetite, and triggers fever.TNF increases vasodilation and loss of vascular permeability and helps the recruitment of lymphocytes, neutrophils, and monocytes to the sites of inflammation by regulating the release of chemokines. Normally, low levels of TNF- alpha are present in plasma, which has the effect of enhancing antiviral, anti-tumor, and anti-infection ability.

TNFR 2 is unable to directly induce programmed cell death by lacking a death domain. Upon full activation of TNFR 2 by tm TNF- alpha, it recruits TRAF through its TRAF domain and activates Complex I formation, enabling NF- κ B and MAPKs as well as AKT activation. TNFR 2 activation is associated with homeostatic bioactivity, for example, tissue regeneration, cell proliferation, and cell survival, as well as host defense and inflammation. The TNF- alpha / TNFR 2 pathway increased expression of CD4, CD25 T cell Foxp 3, and production of latent TGF- β in Tregs and enhanced the immunosuppressive function of Tregs. Heterogeneous ribonucleoprotein K (hnRNPK) acts downstream of TNF alpha -TNFR 2 signaling, directly interacting with target gene promoters and stabilizing the YAP genes throughout the genome, thus centrally regulating the expression of YAP target genes.

Fig 1: TNFR2 Gene Pathway. (Reference documentation: Bai J, Ding B, Li H. Targeting TNFR2 in Cancer: All Roads Lead to Rome. Front Immunol. 2022 Feb 17;13:844931.)

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