Death receptor 3: A paradoxical biomarker and therapeutic target in pan-cancer

Death receptor 3 (DR3/TNFRSF25) is a member of the tumor necrosis factor receptor superfamily, exhibiting dual roles in regulating tumor apoptosis and metastasis. Through literature review and pan-cancer analysis, this study reveals that DR3 expression exhibits distinct tumor type specificity: it is highly expressed in seven cancers, including Bladder Urothelial Carcinoma (BLCA), while showing low expression in sixteen cancers, such as Adrenocortical carcinoma (ACC). Its expression correlates with CD8⁺ T cell and natural killer (NK) cell infiltration, tumor mutational burden (TMB), and is closely associated with prognosis, exhibiting opposite trends across different cancer types. Mechanistically, DR3 activates apoptosis or programmed necrosis pathways by binding its ligand TL1A. Its interaction with NF-κB exhibits directional discrepancies across cancer types, which differentially regulate cell death. Additionally, DR3 suppresses angiogenesis and modulates antitumor immune responses. While multiple natural and synthetic compounds modulate DR3-related pathways to exert antitumor effects, no direct-targeting drugs are currently available. The presence of DR3 isoforms and decoy receptor DcR3 adds complexity to its signaling, suggesting that future clinical applications require precise evaluation considering the tumor microenvironment. In summary, DR3 is a multifunctional molecule with significant potential as a biomarker and therapeutic target. However, its duality and context-dependent effects necessitate the development of personalized strategies based on tumor molecular subtyping.