TNFRSF10C (TNF receptor superfamily member 10c) is a decoy receptor for TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) located at chromosome 8.3. Unlike pro-apoptotic TRAIL receptors, TNFRSF10C lacks a cytoplasmic death domain and functions as a competitive antagonist, protecting cells from TRAIL-mediated apoptosis by sequestering the ligand 1. TNFRSF10C is frequently inactivated in multiple cancers through complementary genetic and epigenetic mechanisms. In prostate cancer, 78% of tumors exhibit promoter CpG island hypermethylation and 74.5% show hemizygous deletion, with 94.9% displaying one or both alterations—inactivation correlates with reduced mRNA expression and enhanced tumor development 2. Similar hypermethylation-driven inactivation occurs in pancreatic cancer, promoting tumor progression 3. In osteosarcoma, low TNFRSF10C expression associates with poor patient outcomes 4. Beyond cancer, TNFRSF10C upregulation has been identified in inflammatory conditions: it is among hub genes positively correlated with neutrophils in thyroid eye disease 5, and G-CSF elevates TNFRSF10C expression in neutrophils during hidradenitis suppurativa, contributing to neutrophil survival and skin-destructive inflammation 6. TNFRSF10C methylation status shows promise as a diagnostic biomarker for cancer detection.