Unlocking the potential of TNF: From biologic agents to small-molecule inhibitors

Tumor necrosis factor (TNF) is a multifunctional cytokine that plays a central role in inflammation and autoimmune diseases. While TNF-neutralizing biologics have transformed treatment paradigms, their limitations, including parenteral administration, high cost, and immunogenicity have driven intensive efforts to develop oral small-molecule inhibitors. This review provides a comprehensive overview of small-molecule TNF/TNFR inhibitors, focusing on three major design strategies: disruption of TNF trimer formation, allosteric stabilization of an asymmetric receptor-incompetent TNF conformation, and direct TNFR binding. We also present a quantitative comparative assessment of affinity versus toxicity across synthetic small molecules, cyclic peptides, and natural products. Critical translational considerations are evaluated, including pharmacokinetic optimization strategies for improving oral bioavailability and metabolic stability; the synergistic potential of combining small-molecule inhibitors with biologics; and systematic off-target analysis using proteomic platforms and cellular assays to predict safety liabilities. By integrating mechanistic insights with emerging translational data, this review provides a roadmap for developing next-generation TNF inhibitors with improved efficacy and safety profiles.