Promising TNF-α inhibitors: Targeting pathogenic TNF-α/TNFR signaling to restore Th17/Treg balance in rheumatoid arthritis

The pleiotropic regulatory effect of tumor necrosis factor-alpha (TNF-α), an essential cytokine involved in immune regulation, is of significant importance in the immune response. TNF-α inhibitors have been widely used in rheumatoid arthritis (RA) and other autoimmune diseases since their introduction into clinical practice. However, the tradeoff between its excellent efficacy and adverse drug reactions (ADR) remains a problem. T cells, especially the T helper cell 17 (Th17)/regulatory T (Treg) cells balance, are crucial for the treatment of autoimmune diseases including RA. This review explores the mechanisms by which TNF-α/TNF receptor (TNFR) signaling induces Th17/Treg imbalance in RA. This review synthesizes current knowledge to facilitate an improved understanding of the causes of ADR, such as infection caused by TNF-α inhibitors in clinical practice. Moreover, our findings offer a reference for exploring potential TNF-α/TNFR signaling inhibitory strategies from the perspective of regulating T cell balance.