The IL-12 Family of Cytokines: Dual Roles in Rheumatic Diseases and Cancer Immunotherapy

Introduction

The IL-12 family comprises structurally similar yet functionally diverse cytokines that play pivotal roles in immune regulation. This family includes IL-12, IL-23, IL-27, IL-35, and IL-39, which modulate the differentiation of helper T cells (such as Th1 and Th17) through distinct receptor signaling pathways, thereby influencing autoimmune diseases, tumor immunity, and infectious diseases. Among them, IL-12 and IL-23 have garnered significant attention due to their extensive clinical applications. This article systematically reviews the structural characteristics, biological functions, and clinical advances of the IL-12 family in rheumatic diseases and cancer immunotherapy.

1. Structural and Functional Features of the IL-12 Family

1.1 Molecular Structure and Receptor Composition

IL-12 family members are heterodimeric cytokines formed by different α and β chains:

IL-12: Composed of p35 (IL-12A) and p40 (IL-12B), it signals through the IL-12Rβ1 and IL-12Rβ2 receptor complex.

IL-23: Consists of p19 (IL-23A) and p40 (IL-12B), binding to the IL-12Rβ1/IL-23R receptor.

IL-27: Formed by p28 (IL-27) and EBI3 (Epstein-Barr virus-induced gene 3), it interacts with the WSX-1 (IL-27Rα) and gp130 receptors.

IL-35: A dimer of p35 (IL-12A) and EBI3, primarily acting on regulatory T cells (Tregs) to exert immunosuppressive effects.

IL-39 (less studied): Composed of p19 and EBI3, potentially involved in inflammatory responses.

Although IL-12 and IL-23 share the p40 subunit, their biological effects differ significantly:

IL-12 promotes Th1 differentiation, enhances IFN-γ production, and strengthens anti-tumor and anti-infection immunity.

IL-23 drives Th17 polarization, inducing IL-17A, IL-17F, and IL-22 secretion, which are closely linked to autoimmune diseases such as psoriasis and rheumatoid arthritis.

1.2 Signaling Pathways and Immune Regulation

IL-12/STAT4 Pathway: IL-12 activates the JAK2/TYK2-STAT4 axis, promoting Th1 polarization and enhancing cytotoxic T cell (CTL) and NK cell-mediated anti-tumor responses.

IL-23/STAT3 Pathway: IL-23 signals via JAK2-STAT3 to expand Th17 cells, contributing to the pathogenesis of inflammatory bowel disease (IBD), psoriasis, and other autoimmune disorders.

2. Therapeutic Applications of the IL-12 Family in Rheumatic Diseases

Given the critical role of IL-23 in Th17-mediated autoimmunity, monoclonal antibodies targeting IL-12/IL-23 p40 or IL-23 p19 have become cornerstone therapies for rheumatic diseases.

2.1 Anti-p40 Monoclonal Antibodies

Ustekinumab

Mechanism: Binds the shared p40 subunit of IL-12 and IL-23, blocking interaction with IL-12Rβ1 and suppressing Th1/Th17 responses.

Indications:

Plaque psoriasis (FDA-approved in 2009)

Psoriatic arthritis (PsA)

Crohn’s disease (CD)

Advantages: Sustained efficacy and favorable safety profile.

2.2 Anti-IL-23 p19 Monoclonal Antibodies

Since IL-23 specificity is determined by its p19 subunit, selective p19 inhibitors offer more precise Th17 modulation with fewer off-target effects. Approved p19 inhibitors include:

Guselkumab

First-in-class IL-23 p19 inhibitor (FDA-approved in 2017).

Superior to TNF-α inhibitors (e.g., adalimumab) and IL-17A blockers (e.g., secukinumab) in psoriasis.

Tildrakizumab

Approved in the EU (2018) for moderate-to-severe psoriasis.

Convenient dosing (subcutaneous injection every 3 months).

Risankizumab

Approved in 2019 for psoriasis and Crohn’s disease.

Mirikizumab

Phase III trials for ulcerative colitis (UC) and Crohn’s disease (CD).

2.3 Future Directions

Dual-target inhibitors: Simultaneous blockade of IL-12 and IL-23 may enhance efficacy but requires careful safety evaluation.

Personalized therapy: Tailoring treatments based on individual Th1/Th17 immune profiles.

3. IL-12 in Cancer Immunotherapy

IL-12’s potent Th1-stimulating properties make it a promising candidate for cancer immunotherapy. Current strategies include:

3.1 Gene Therapy and Local Delivery

Ad-RTS-hIL-12 (NCT02026271):

Adenoviral vector for controlled IL-12 expression in glioblastoma.

Combined with veledimex to regulate IL-12 levels in the tumor microenvironment.

Electroporation-mediated IL-12 plasmid (Tavo + PD-1 inhibitor):

Intratumoral IL-12 DNA (tavokinogene telseplasmid) with pembrolizumab (Keytruda) for melanoma (NCT03132675).

3.2 Combination with Immune Checkpoint Inhibitors (ICIs)

MEDI1191 (IL-12 mRNA vaccine + Durvalumab) (NCT03946800):

Early data show enhanced anti-tumor activity with PD-L1 blockade and good tolerability.

IL-12 fusion proteins (e.g., IL12-L19L19) (NCT04471987):

Tumor-targeted IL-12 delivery via L19 antibody to minimize systemic toxicity.

3.3 Challenges and Optimization

Toxicity management: Systemic IL-12 can cause severe inflammation, necessitating localized delivery (e.g., intratumoral injection).

Combination strategies: Synergizing with CAR-T, oncolytic viruses, etc., to improve immune infiltration.

4. Conclusion and Future Perspectives

The IL-12 family exhibits dual immunomodulatory roles:

The IL-23/Th17 axis is a key target in autoimmune diseases, with p19 inhibitors now first-line therapies for psoriasis and IBD.

The IL-12/Th1 axis holds great potential in cancer immunotherapy but requires advances in delivery systems.

Future research should focus on:

Developing precision IL-12 delivery platforms (e.g., nanocarriers, conditional expression vectors).

Exploring the functions of lesser-studied members (e.g., IL-35, IL-39).

Optimizing combination therapies to enhance clinical outcomes in autoimmunity and oncology.

With ongoing biotechnological innovations, the IL-12 family will continue to unlock new frontiers in immunotherapy.

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