Unfolding transmembrane TNFα dynamics in cancer therapeutics

Cytokines are a group of glycoprotein signaling mediators, which play essential roles in maintaining several complex physiological functions of our body. TNFα is such a pleiotropic cytokine, which involves maintaining a plethora of immune responses. Initially, TNFα is synthesized as a 26 kDa full-length transmembrane form, which is enzymatically cleaved to produce the soluble circulating 17 kDa TNFα. Although the anti-cancer potential of soluble TNFα was discovered more than a century back, its dual ability to promote tumor, posed a major hindrance in finding its acceptance as a proper anti-cancer molecule. In contrast, the membrane-tethered tmTNFα holds the potential of tumor regression without initiating cell proliferation. The membrane-tethered form of TNFα is the physiological precursor of soluble TNFα that remains biologically active and is capable of initiating signaling cascades after binding with the TNFα receptors- TNFR I and TNFR II. In this review, we emphasize on the basic biology and molecular aspects of tmTNFα for its anti-cancer potential.