Keywords: IL-23/IL-17 axis, Th17 regulatory network, pathway crosstalk, bispecific antibodies, oral cyclic peptides

IL-23 and IL-17A do not function in isolation but form a complete signaling axis from innate to adaptive immunity and from antigen presentation to tissue inflammation. Key components of this axis include: IL-23 activates the STAT3-RORγt transcriptional program via IL-23R, driving Th17 cell differentiation; Th17 cells secrete IL-17A and IL-17F; IL-17A activates the NF-κB and MAPK pathways in target tissues through IL-17RA/IL-17RC, inducing inflammatory gene expression. Additionally, this axis is regulated by cytokines such as TGF-β, IL-6, and IL-1β and exhibits crosstalk with pathways like TNF-α and IL-22. This article analyzes the regulatory logic of the IL-23/IL-17A signaling axis from a network perspective and explores the molecular basis for multi-target interventions.

The IL-23/IL-17A signaling axis can be divided into three functional layers:

Induction layer: Antigen-presenting cells (dendritic cells, macrophages) produce IL-23 via the TLR-MyD88 pathway upon receiving pathogen or inflammatory signals. TGF-β, IL-6, and IL-1β synergistically provide the initial signals for Th17 differentiation in naive CD4+ T cells.

Amplification and maintenance layer: IL-23 acts on differentiated Th17 cells, upregulating IL-23R expression via STAT3 signaling to form a positive feedback loop while promoting RORγt and IL-17A transcription. The core of this layer is the IL-23/STAT3/RORγt/IL-23R self-enhancing circuit.

Effector layer: Th17 cells secrete IL-17A, IL-17F, and IL-22, acting on target tissue stromal cells (keratinocytes, fibroblasts, epithelial cells) to induce chemokines CXCL1/CXCL8/CCL20, recruiting neutrophils and more Th17 cells, forming an inflammatory amplification loop.

Cross-regulation exists between the three layers: IL-1β and IL-6 produced in the effector layer can feedback-enhance Th17 polarization in the induction layer; chemokines released by target tissues further recruit circulating Th17 cells, amplifying local inflammation.

RORγt is the defining transcription factor for the Th17 lineage and lies at the core of this axis. RORγt activity is directly transcriptionally regulated by STAT3 and influenced by post-translational modifications (e.g., phosphorylation, acetylation). RORγt antagonists can suppress IL-17A production without affecting other T cell lineages, representing an important direction for small-molecule intervention.

STAT3 is the primary downstream effector of IL-23 signaling and the critical link between IL-23 and RORγt. STAT3 plays multiple roles in Th17 differentiation: inducing RORγt expression, upregulating IL-23R, and suppressing Treg-related genes (Foxp3). The SH2 domain and DNA-binding domain of STAT3 are potential drug targets.

NF-κB dominates the downstream effects of IL-17A signaling. However, NF-κB is a widely used transcription factor, and its inhibitors lack pathway selectivity. The specificity of IL-17 signaling relies more on proximal adaptor proteins like Act1 and TRAF6.

IL-23 and TNF-α: TNF-α can induce dendritic cells to produce IL-23, while IL-23 enhances T cell sensitivity to TNF-α. Their synergistic effect is particularly prominent in synovial inflammation in rheumatoid arthritis. Dual-targeting strategies against TNF-α/IL-23 are under preclinical exploration.

IL-23 and IL-22: IL-22 is co-produced by Th17 cells but acts on epithelial cells to promote barrier repair. In certain disease contexts (e.g., inflammatory bowel disease), IL-22 has protective effects. Thus, IL-23 inhibition may downregulate IL-22, indirectly affecting barrier function—a factor to consider when targeting upstream.

IL-17A and TNF-α: At the target cell level, IL-17A and TNF-α synergistically induce inflammatory gene expression. They activate distinct downstream pathways (NF-κB vs. MAPK) and can enhance signal strength via cross-phosphorylation. Clinically, some patients unresponsive to anti-TNF therapy still respond to anti-IL-17, suggesting functional redundancy and compensation between the two pathways in certain patients.

Compensatory Th17 activation: In some models, IL-1β can directly drive Th17 differentiation without IL-23 after IL-23 blockade. This compensatory mechanism may underlie primary resistance to IL-23 inhibitors in some patients.

Based on the hierarchical structure and crosstalk features of the pathway, several dual-targeting strategies have been proposed:

(1) IL-17A/F dual targeting: Simultaneously neutralizing IL-17A and IL-17F. IL-17F shares the receptor subunit IL-17RA with IL-17A but has lower affinity. In some diseases, IL-17F can compensate for IL-17A deficiency. The dual-targeting antibody bimekizumab has demonstrated superiority over single-target IL-17A antibodies.

(2) IL-23p19/TL1A dual targeting: TL1A, a TNF family member, synergizes with IL-23 to promote Th17 pathogenicity in inflammatory bowel disease. Bispecific antibodies blocking both targets theoretically cover a broader range of pathogenic pathways.

(3) IL-23/IL-17 dual neutralization: Since the two targets reside at different layers, simultaneous blockade can suppress both Th17 differentiation and effector functions. Technically, this can be achieved via bispecific antibodies or antibody-ligand trap fusion proteins.

(4) RORγt + IL-23R combination: Small-molecule RORγt inverse agonists combined with anti-IL-23 antibodies can dually suppress the Th17 pathway at transcriptional and signaling levels.

As a transmembrane receptor, the extracellular ligand-binding domain of IL-23R is targetable. Traditionally occupied by monoclonal antibodies, the approval of the first oral IL-23R antagonist cyclic peptide, Icotrokinra, in 2026 marked a milestone in small-molecule/peptide intervention for extracellular receptor domains.

Design principle of cyclic peptides: The constrained cyclic structure mimics the IL-23 p19 subunit's interaction interface with IL-23R, competitively blocking ligand-receptor binding. Oral bioavailability challenges were addressed via N-methylation, cyclization stability, and permeability optimization.

The significance of this approach lies in transforming traditionally injectable receptor blockers into oral drugs while maintaining high affinity and selectivity. Oral IL-23R antagonists and anti-IL-17 monoclonal antibodies complement each other mechanistically—the former acts upstream, the latter downstream; the former is an oral small molecule (cyclic peptide), the latter an injectable biologic.

Research on the IL-23/IL-17A signaling axis provides multi-faceted insights for autoimmune drug development:

First, different nodes of the same pathway can yield mechanistically complementary drugs. Upstream (IL-23) and downstream (IL-17A) targeting differ clinically, representing complementary rather than substitutive approaches.

Second, pathway complexity suggests single targets may not suffice for all patient populations. Multi-target strategies (bispecific antibodies, combination therapies) are inevitable for broader coverage.

Third, the evolution from monoclonal antibodies to oral cyclic peptides demonstrates that the targetable space of extracellular receptor domains remains underexplored by small molecules/peptides. Novel chemical entities may break traditional biologic delivery limitations.

Finally, regulatory proteins in the pathway (Act1, RORγt, STAT3) represent potential sources for next-generation targets, particularly suited for small-molecule intervention.

The IL-23/IL-17A signaling axis is a well-structured hierarchical regulatory network, forming a complete signal transmission chain from innate immune sensing to T cell differentiation and tissue inflammatory effects. A systematic understanding of this network not only explains the mechanisms and limitations of current drugs but also provides a theoretical framework for next-generation multi-target strategies, oral small-molecule interventions, and pathway-selective regulation. As one of the most successful target systems in autoimmune research, its paradigm will also inform drug development for other inflammatory pathways.