Autoimmune Disease Landscape: IL-12/IL-23 Biological Functions and Evolving Targeted Therapies

At the core of autoimmune disease lies a dysregulated immune system that mistakenly attacks self-tissues. Among the key regulators of this process are interleukin-12 (IL-12) and interleukin-23 (IL-23), a closely related cytokine pair that shares structural homology yet exerts distinct immunological functions. These cytokines not only drive pathogenic inflammatory responses, but also play essential roles in maintaining immune homeostasis.

A recent review published in Nature Reviews Immunology highlights the dual biological roles of IL-12 and IL-23, challenging the longstanding view that they function solely as pro-inflammatory mediators. The study further advances the development of precision-targeted therapies and offers renewed therapeutic promise for patients with autoimmune diseases such as Psoriasis and Inflammatory Bowel Disease.

Shared Origins, Distinct Functions: The Structure and Biology of IL-12 and IL-23

IL-12 and IL-23 belong to the IL-12 cytokine family and can be viewed as "molecular siblings" that share the common p40 subunit backbone. However, their unique partner subunits confer distinct biological activities, positioning them as central regulators of divergent immune responses and key therapeutic targets in autoimmune diseases.

Schematic representation of IL-12 and IL-23 subunits, their receptors and proximal signal transduction

- IL-12 is composed of the shared p40 subunit and the unique p35 subunit, functioning as both a pro-inflammatory and immunoregulatory cytokine. Depending on the tissue context and stage of inflammation, IL-12 can also exert protective effects. Its primary role is to drive the differentiation of naïve T cells into Th1 cells and stimulate IFN-γ production, thereby orchestrating immunity against intracellular pathogens and tumors. However, aberrant or sustained IL-12 activation can contribute to autoimmune inflammation under pathological conditions.

- In contrast, IL-23 represents a predominantly pro-inflammatory cytokine, consisting of the shared p40 subunit and the unique p19 subunit. Rather than initiating T-cell differentiation, IL-23 primarily promotes the expansion and stabilization of Th17 cells. Through activation of the STAT3 signaling pathway, IL-23 induces the production of effector cytokines such as IL-17, IL-22, and GM-CSF, which are key drivers of chronic inflammation and autoimmune disease pathogenesis. Under physiological conditions, IL-23 also contributes to the maintenance of mucosal barrier integrity, whereas dysregulated signaling can lead to persistent tissue damage and chronic inflammatory injury.

- Their receptor systems similarly reflect both "shared" and "distinct" features. IL-12 and IL-23 both utilize IL-12Rβ1 as a common signaling component, while IL-12 specifically engages IL-12Rβ2 and IL-23 uniquely binds IL-23R. These receptor differences provide a strong molecular foundation for the development of highly selective targeted therapies.

Disrupted IL-12/IL-23 Homeostasis: Mechanistic Drivers of Autoimmune Inflammation

The coordinated regulation of IL-12 and IL-23 is essential for preserving immune homeostasis. Aberrant activation or imbalance of these cytokines contributes to the pathogenesis of multiple autoimmune disorders through distinct yet interconnected inflammatory pathways. Importantly, IL-12 and IL-23 exhibit disease-specific immunopathological functions across different autoimmune settings, representing a key concept emphasized in this Nature review.

Opposing functions of IL-12 and IL-23 in psoriasiform inflammation

In cutaneous inflammatory disorders, IL-23 is recognized as a central pathogenic driver of psoriasis, primarily mediating epidermal injury through induction of IL-17 and IL-22 signaling. In contrast, IL-12 appears to exert tissue-protective and immunoregulatory functions by limiting excessive inflammatory responses, although some studies suggest that it may also contribute to disease pathogenesis under specific conditions. This functional divergence may explain why selective IL-23p19-targeted therapies, such as Guselkumab, have demonstrated superior clinical efficacy compared with agents targeting the shared p40 subunit of both IL-12 and IL-23, such as Ustekinumab.

In intestinal inflammation, hyperactivation of the IL-23/Th17 axis is a major pathogenic driver of inflammatory bowel disease, including Crohn's Disease and Ulcerative Colitis. Dysregulated IL-23 signaling promotes chronic mucosal injury and ulceration within the gastrointestinal tract. IL-12, meanwhile, contributes to the regulation of immune tolerance, and impaired IL-12 signaling may further sustain intestinal inflammation and hinder mucosal repair.

In systemic autoimmune diseases, the IL-23/Th17 axis plays a pivotal role in the pathogenesis of Lupus Nephritis, where it can synergize with type I interferon signaling to exacerbate renal tissue injury. IL-12 may additionally influence disease activity in Systemic Lupus Erythematosus by modulating the balance between Th1 and Th17 cell subsets. Beyond these conditions, IL-23 is also broadly implicated in synovial inflammation and bone destruction in spondyloarthropathies such as Psoriatic Arthritis and Ankylosing Spondylitis, highlighting its importance as a therapeutic target in these diseases.

Precision Targeting, Therapeutic Innovation: Clinical Advances in IL-12/IL-23-Targeted Therapies

Driven by the distinct structural features and pathological functions of IL-12 and IL-23, therapeutic development has evolved from non-selective dual-cytokine blockade toward highly selective single-target modulation. In recent years, significant advances have been achieved in indication expansion, innovative domestic drug development, and clinical efficacy, providing patients with increasingly precise and individualized treatment strategies.

Early dual-target blockade strategies, such as monoclonal antibodies directed against the shared p40 subunit, were designed to simultaneously inhibit both IL-12 and IL-23 signaling. Although these agents demonstrated clinical efficacy in diseases such as psoriasis and Crohn's Disease, their lack of selectivity was associated with disruption of normal immune function, potentially increasing the risk of infections and malignancies.

Ustekinumab was the first fully human dual-target IL-12/IL-23 inhibitor approved globally. By specifically binding the shared p40 subunit, it blocks downstream signaling of both cytokines and has been widely adopted for the treatment of adult psoriasis. Subsequent approval for pediatric and adolescent psoriasis has further expanded its clinical utility across broader patient populations.

With increasing insight into the distinct pathogenic roles of IL-12 and IL-23, the field has shifted toward selective single-target therapeutic strategies. Agents targeting the IL-23 p19 subunit selectively inhibit IL-23 signaling while preserving IL-12-mediated host immune defense, thereby suppressing chronic inflammation with a substantially improved safety profile.

- Among these, Guselkumab, an IL-23 p19 monoclonal antibody indicated for adults with moderate-to-severe plaque psoriasis, has gained broad clinical recognition worldwide. Its convenient once-every-8-weeks dosing regimen, combined with robust and durable efficacy, enables effective control of skin lesions and reduction of disease recurrence.

- In parallel, therapies targeting the IL-12 p35 subunit are being developed primarily for diseases associated with aberrant IL-12 activation, enabling a more disease-specific and precision-based therapeutic approach while avoiding the limitations of non-selective, "one-size-fits-all" immunosuppression.

Future Perspectives: Balancing IL-12/IL-23 Signaling to Unlock Novel Immunotherapeutic Opportunities

This Nature review redefines IL-12 and IL-23 as cytokines with both pro-inflammatory and tissue-protective functions, highlighting a shift in immunotherapy from broad systemic blockade toward tissue-specific precision modulation aimed at suppressing pathological inflammation while preserving physiological immune defense. Future advances are expected to focus on engineered next-generation cytokines, biomarker-driven patient stratification, optimized combination therapies, and localized drug delivery strategies.

IL-12/IL-23 Target Reagents: Enabling Autoimmunity Mechanism & Therapy Development

Reference

Rindlisbacher L, Navarro M N, Becher B. Inflame and restrain---the paradoxical roles of IL-12 and IL-23 in immunity[J]. Nature Reviews Immunology, 2026: 1-12. https://doi.org/10.1038/s41577-025-01255-1