Emerging insights into TL1A biology may guide precision therapy for IBD

A key feature positioning TL1A as a premier therapeutic target for IBD is its potent function as a synergistic signal amplifier. Thus, rather than targeting a single cytokine pathway, TL1A blockade broadly dampens signals from inflammatory cues in a site-specific and context-specific fashion. While TL1A signaling via the death receptor 3 (DR3) leads to both mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) activation of effector cytokines (Hedl and Abraham, 2014; Bamias et al., 2025), the molecular factors that enable TL1A to synergize with additional tissue factors, including IL-23 or bacterial-derived signals, are less clear. Recent work from our group identified the transcription factor Basic Helix-Loop-Helix family member E40 (BHLHE40) as a key TL1A-induced factor that shapes DR3-driven synergistic signals across innate intestinal RORγt⁺ cell populations (Yang et al., 2026) (Fig. 1). In ILC3s, BHLHE40 functions as both a transcriptional and epigenetic checkpoint governing tissue immunity in a cytokine-specific manner. As such, BHLHE40 functions as a context-dependent regulator, supporting mucosal protection during infection while driving pathogenic cytokine programs in innate models of colitis. Although broadly expressed across lymphoid and myeloid lineages, the cytokine-specific regulatory effects in ILC3s enable a cell type–restricted effect that affords tissue-dependent transcriptional control. In this framework, BHLHE40 serves as a molecular link underlying TL1A’s amplifier function, acting as dual transcriptional and epigenetic integrator that fine-tunes tissue responses depending on inflammatory context, and may itself represent a tractable therapeutic target.

The identification of Bhlhe40 as a TL1A-induced target in ILC3s also uncovered its expression in an emerging group of RORγt⁺ APCs, which play a critical role in coordinating peripheral regulatory T cell (pTreg) development (Abramson et al., 2024; Kedmi and Littman, 2024; Cabric and Brown, 2025). Deletion of Bhlhe40 in RORγt⁺ APCs reduced Itgb8 expression and impaired antigen-specific pTreg generation, revealing the broader role for this pathway in mucosal immunity. We further identified OX40L as an additional BHLHE40 target regulating pTreg induction; however, OX40L was not expressed by RORγt⁺ APCs, but rather ILC3s. These findings reveal a new model in which a TL1A–BHLHE40–OX40L axis links RORγt⁺ APCs with ILC3s capable of providing the co-stimulation required for efficient induction of gut microbe-specific pTregs to maintain mucosal homeostasis.

While IBD therapy has traditionally focused on specifically targeting intestinal inflammation, IBD is increasingly recognized as a systemic disease with frequent extraintestinal manifestations that reflect a broader immune dysregulation. Emerging evidence suggests that inflammatory signals originating in the tissue can durably reprogram hematopoietic progenitors in the bone marrow, establishing maladaptive innate immune memory that persists beyond active disease (Hajishengallis et al., 2025). Such long-lived changes in hematopoietic output may contribute to disease recurrence, treatment resistance, and extraintestinal manifestations.

A recent study now positions TL1A within this framework, proposing that it functions not only as a regulator of tissue immunity but also as a driver of inflammatory hematopoietic output (Pires et al., 2026) (Fig. 1). Using a colitis-associated tumor model in mice, TL1A-stimulated ILC3 promoted tumorigenesis by skewing neutrophils to a tumor-promoting phenotype. These findings were further confirmed in IBD-associated dysplasia and in UC patients treated with anti-TL1A therapy. Notably, TL1A-stimulated ILC3s and its downstream induction of GM-CSF were necessary and sufficient to drive induction of Cebpb in granulocyte-monocyte progenitors (GMPs) and emergency granulopoiesis, establishing a mechanistic link between intestinal inflammation and altered bone marrow output (Pires et al., 2026). Together, these findings reveal a TL1A-ILC3-GM-CSF axis linking intestinal inflammation to emergency granulopoiesis and inflammatory neutrophil output, with potential to shape long-lived epigenetic and metabolic remodeling of GMPs.

These findings raise the possibility that TL1A can act as a central coordinator of maladaptive inflammatory hematopoiesis. Beyond driving transient emergency granulopoiesis, persistent TL1A signaling may induce durable epigenetic and metabolic remodeling, locking progenitors in an inflammatory state. Such a mechanism would position TL1A upstream of maladaptive trained immunity, enabling chronic intestinal inflammation to reshape future myeloid responses long after the initial inflammatory trigger has subsided. Whether TL1A directly contributes to the establishment or maintenance of trained hematopoietic states remains unknown, but represents an important area for future investigation.

As anti-TL1A therapies advance through late-stage clinical trials, these observations raise a fundamental translational question: are these agents simply dampening intestinal inflammation or intercepting a systemic process of maladaptive immune reprogramming? If the latter proves true, the therapeutic impact of TL1A blockade may redefine how we approach extraintestinal disease, therapeutic timing, and the goal of long-term immune restoration in IBD.

No pharmacological agents currently available target fibrostenotic CD, which represents one of the most significant unmet needs in IBD. Polymorphisms in TNFSF15 correlate with more aggressive stricturing disease and underscore a potential link between TL1A and fibrogenesis (Longman, 2026). Preclinical overexpression studies have demonstrated expansion of fibroblasts and myofibroblasts in experimental models of colitis, driven through direct DR3 signaling on stromal cells via Rho-dependent pathways (Jacob et al., 2020). While this fibrogenic program depends on specific bacterial signals, it surprisingly operates independently of effector lymphocytes, highlighting TL1A as a potential direct mediator of intestinal fibrosis. Consistent with these findings, DR3 expression has been confirmed on tissue myofibroblasts in human IBD specimens, demonstrating the potential importance of a dual anti-inflammatory and anti-fibrotic effect of TL1A/DR3 blockade as a therapeutic class.

Genetic polymorphisms in TNFSF15 confer susceptibility to CD, and functional studies demonstrate that disease-associated haplotypes correlate with increased TL1A protein expression (Bilsborough and Targan, 2024). While this raised the exciting possibility that a companion diagnostic test could guide patient stratification for anti-TL1A therapy in IBD, initial phase 2 reports did not reveal a clear clinical benefit from the companion diagnostic tested. A more refined multi-biomarker strategies may offer better resolution, including the incorporation of T cell activation states, transcriptional markers regulated by BHLHE40, and neutralizing antibodies to GM-CSF—the latter having emerged as a biomarker of CD that may help identify patients with GM-CSF–dependent inflammatory pathways most likely to respond to TL1A-directed therapy. Intriguingly, recent data confirm a skewing of hematopoiesis in subjects carrying TNFSF15 risk polymorphisms even during inactive disease (Pires et al., 2026), suggesting that TL1A pathway activity leaves a measurable impact on granulopoiesis that could serve as a pathway-specific biomarker.

With multiple anti-TL1A assets on the cusp of completing phase 3 trials, the field is entering a new phase. If clinical results in UC prove promising, attention will shift rapidly from whether these therapies work to why they work, how to optimize their use, how to track their efficacy, and how to identify patients most likely to benefit. The mechanistic framework reviewed here, encompassing molecular, cellular, and context-specific transcriptional regulation, hematopoietic reprogramming, stromal fibrogenesis, and genetically stratified immune programs, provides a rich substrate for that next generation of translational inquiry. A deeper understanding of TL1A biology will not only guide the implementation of this new therapeutic class but may also chart a path toward precision medicine for IBD more broadly.

Author contributions: Silvia Pires: conceptualization, visualization, and writing—original draft, review, and editing. Wei Yang: conceptualization, visualization, and writing—original draft, review, and editing. Randy S. Longman: conceptualization, funding acquisition, and writing—original draft, review, and editing.