Targeting TNFR1-driven necroptosis in breast cancer.

Tumor Necrosis Factor Receptor 1 (TNFR1) plays a crucial role in determining whether a breast cancer cell will survive, undergo natural cell death, or die through necroptosis. It influences these outcomes via pathways such as NF-kB, caspase-8, and the RIPK1-RIPK3-MLKL axis. TNFR1 activation causes epigenetic changes in DNA methylation, histone modification, and chromatin remodeling, which reprogram cellular responses to death signals. The direct and indirect epigenetic events leading to TNFR1-mediated cell death include DNMT enrolment, H3K4me3/H3K27ac changes, and microRNA-mediated controls. TNFR1 signaling regulates DNA methyltransferase activity and histone acetyltransferases while controlling epigenesis through metabolic reprogramming and non-coding RNA networks. The necroptotic execution pathway, triggered by pro-survival complex degradation and caspase-8 inhibition, forms the RIPK1-RIPK3 necrosome, phosphorylates MLKL, and releases damage-associated molecular patterns. TNF dual role of TNF signaling in tumor growth, necroptosis, and inflammatory remodeling presents therapeutic challenges. Biomarkers include TNFR1 expression, RIPK1/RIPK3 phosphorylation, MLKL localization, and epigenetic markers. Therapeutic combinations of epigenetic modulators, SMAC mimetics, RIPK1, and immune checkpoint inhibitors show promise in overcoming treatment resistance. Challenges in patient stratification, drug sequencing, and management of inflammatory toxicity require urgent solutions. This review provides a basis for clinical trials targeting the TNFR1-necroptosis pathway with biomarker-guided therapies and epigenetic strategies for breast cancer therapy. See also the graphical abstract(Fig. 1).