TL1A-DR3 Signaling in Inflammatory Bowel Disease: From Pathogenesis to Therapeutic Targeting.
TNF-like cytokine 1A (TL1A) and its receptor DR3 form a key regulatory axis within mucosal immunity, integrating signals that promote Th1/Th17 responses, modulate innate lymphoid cells, and influence epithelial repair. Beyond inflammation, TL1A directly activates intestinal fibroblasts and contributes to extracellular matrix deposition, positioning the TL1A-DR3 pathway as a central driver of both chronic inflammation and fibrosis in inflammatory bowel disease (IBD). Genetic variants in TNFSF15, which encodes TL1A, further support a causal role, linking increased TL1A expression with susceptibility to Crohn's disease, ulcerative colitis, and fibrostenotic complications. Recent clinical trials of TL1A-neutralizing antibodies, including afimkibart, tulisokibart, and duvakitug, have demonstrated encouraging efficacy and safety in moderate-to-severe IBD, with emerging biomarker strategies suggesting potential for personalized treatment. Collectively, current evidence highlights TL1A blockade as a promising dual-pathway therapeutic approach targeting inflammation and fibrotic remodeling, with ongoing studies expected to define its long-term impact on disease modification.