TNFRSF10D (TRAIL receptor 4) is a cell surface receptor for the cytotoxic ligand TRAIL. Unlike death-inducing TRAIL receptors, TNFRSF10D contains a truncated intracellular death domain and cannot trigger apoptosis 1. Instead, it functions as a decoy receptor that protects cells against TRAIL-mediated apoptosis 1. Evidence regarding NF-κB pathway activation remains contradictory: one study reports TNFRSF10D can activate NF-κB, while another indicates it cannot. Despite its defective apoptotic signaling, TNFRSF10D can activate NF-κB through non-canonical TRAIL signaling, potentially promoting pro-inflammatory responses 2. In osteosarcoma, TNFRSF10D is differentially expressed compared to normal cells and is proposed as a therapeutic target for cancer treatment 3. In melanoma, TNFRSF10D promoter methylation silences its expression and may contribute to melanomagenesis 4. Recent work demonstrates that cisplatin treatment dramatically upregulates TNFRSF10D expression in chemoresistant ovarian cancer cells, where the receptor's non-canonical NF-κB activation may promote cell survival and chemoresistance 2. In gastric cancer, quercetin-induced upregulation of TNFRSF10D is associated with apoptotic cell death 5. These findings suggest TNFRSF10D expression patterns serve as a biomarker for cancer aggressiveness and chemotherapy response, with potential therapeutic implications for targeting TRAIL-dependent pathways in resistant tumors.