TNFα signaling at the crossroads of cancer: unveiling dual roles in tumor progression and therapy
image: TNFα-TNFR1 signaling induces pleiotropic responses i.e. activation of transcription factors viz. NF-κB and AP-1 to lead to cell proliferation or induction of apoptosis/necroptosis, depending upon the cellular environment (P: phosphorylated).
Credit: P: phosphorylated
Tumor Necrosis Factor-alpha (TNFα), a pivotal inflammatory cytokine, plays paradoxical roles in cancer—both promoting tumor survival and triggering cell death. A comprehensive review by Sonal M. Manohar and colleagues, published in Current Molecular Pharmacology, dissects TNFα's intricate signaling networks, revealing its dual impact on cancer progression and therapy.
TNFα exerts its effects via two receptors, TNFR1 and TNFR2, activating divergent pathways. TNFR1 triggers NF-κB and MAPK cascades, fostering cell proliferation and inflammation, while also initiating apoptosis or necroptosis under specific conditions. "The balance between TNFα's pro-survival and pro-death signals depends on cellular context, including receptor expression and downstream adaptor proteins," explained Manohar. TNFR2, lacking a death domain, primarily promotes cell survival and tissue repair, complicating TNFα's therapeutic targeting.