Targeting the TL1A pathway in inflammatory bowel disease: mechanistic insights and emerging therapeutic pipeline.

Abstract

Tumor necrosis factor-like ligand 1A (TL1A), encoded by TNFSF15, signals through death receptor 3 on effector T cells, innate lymphoid cells, and intestinal myofibroblasts, driving both chronic intestinal inflammation and tissue fibrosis. In this narrative review, we provide a contemporary appraisal of TL1A-directed therapeutics in inflammatory bowel disease based on electronic searches through May 2026. Three anti-TL1A monoclonal antibodies (tulisokibart, afimkibart, and duvakitug) have advanced to phase 3 trials across multiple global programs, with phase 2 clinical remission rates of 26%-48% in ulcerative colitis (placebo-adjusted differences 15-26 percentage points) and endoscopic response rates of 26%-48% in Crohn's disease, alongside favorable safety profiles. Mucosal transcriptomic and serum proteomic analyses from phase 2 trials, including DDW 2026 readouts from ARTEMIS-UC and TUSCANY-2, provide the first human-tissue confirmation of class antifibrotic activity through the suppression of Th17, myeloid, and extracellular matrix pathways. TNFSF15 risk-variant companion diagnostics are advancing, although their incremental utility remains modest and will be definitively tested in phase 3. The pipeline has expanded to at least 19 development programs, including extended half-life antibodies (XmAb942, SPY002, and BCD-261), bispecifics combining TL1A with IL-23 or α4β7 (RO7837195, XmAb412, LQ080, and ALX001), a first-in-class oral anti-TL1A nanobody, and a first-in-class DR3 receptor antagonist (SL-325). We discuss therapeutic positioning and timing, the opportunity in acute severe UC, and the unusual standing of IBD as the lead indication for this mechanism class. Phase 3 results anticipated in 2026-2027 will be particularly informative for fibrostenotic phenotypes and biologic-refractory patients.