Recent Advances in Cytokines

1. Expanding the Interleukin Family: IL-29 through IL-40+

• IL-36 - gained clinical relevance through spesolimab (anti-IL-36R), approved for generalized pustular psoriasis. IL-36 drives keratinocyte-driven neutrophil recruitment and is now recognized as a distinct pustular inflammation pathway separate from Th17.
• IL-31 - a key pruritogen in atopic dermatitis; nemolizumab (anti-IL-31Rα) was approved in 2024, directly targeting itch at the cytokine level rather than downstream.
• IL-39 - a proposed heterodimer of IL-23p19 + EBI3, implicated in Th17/B-cell activation in experimental lupus and colitis models, but its existence in humans remains controversial.
• IL-40 - associated with B-cell homeostasis and chronic inflammation (rheumatoid arthritis, IBD); still under investigation for its precise function and therapeutic potential.
• IL-24 - a member of the IL-10 family newly shown to signal through JAK-STAT, PI3K-AKT, mTOR, and MAPK pathways, with selective anti-tumor toxicity in cancer cells via endoplasmic reticulum stress induction.

2. JAK-STAT Pathway: The Master Switch

• Brepocitinib (TYK2/JAK1) - showing efficacy in dermatomyositis and psoriasis
• Deucravacitinib (allosteric TYK2 inhibitor) - selectively blocks IL-12/IL-23/IFN-I signaling with improved safety vs. pan-JAK inhibitors
• JAK inhibitors now have evidence in alopecia areata (ritlecitinib, baricitinib), non-infectious uveitis, and vitiligo

3. Type 2 Cytokines and Precision Biologics for Allergic Disease

4. Cytokines in IBD: Combination Blockade Era

• Anti-IL-23 agents (risankizumab, guselkumab, mirikizumab) - now approved for Crohn's and ulcerative colitis based on the validated central role of IL-23 (not IL-12) as the driver
• Combination strategies - anti-TNF + anti-IL-23 simultaneously showing early synergistic results in trials
• IL-2-induced Treg expansion - low-dose IL-2 to expand regulatory T cells is in clinical trials for IBD and autoimmunity
• JAK inhibitors (tofacitinib, upadacitinib, filgotinib) - approved as multi-cytokine blockers that intercept multiple pathways at once

5. Cytokines in the Tumor Microenvironment

• IFN-γ - anti-tumor; activates MHC-I presentation, essential for T cell killing; but chronic IFN-γ upregulates PD-L1 as a resistance mechanism
• Innate inflammatory cytokines (IL-1β, IL-6, TNF-α) - promote oncogenesis, tumor angiogenesis, and immune evasion in the TME
• IL-10 - being re-evaluated; once thought immunosuppressive in cancer, now shown to activate CD8+ T cells; pegilodecakin (PEG-IL-10) in trials
• IL-2 variants - high-dose IL-2 causes dose-limiting toxicity (capillary leak via IL-2Rα on endothelium); next-generation IL-2 "no-alpha" muteins (bias toward IL-2Rβ/γ) and pegylated IL-2 (bempegaldesleukin) circumvent this, expanding CD8+ T cells without Treg or endothelial stimulation
• Targeted cytokine delivery - tumor-localized cytokine fusion proteins (e.g., IL-12 fused to tumor-targeting antibody fragments) undergoing Phase II trials

6. Engineered and Synthetic Cytokines (Frontier Area 2025-2026)

• "Inducikines" - cytokines engineered with molecular sensors that remain inactive until they enter the tumor microenvironment (e.g., detecting hypoxia or specific tumor antigens). This aims to solve the long-standing toxicity problem of systemic cytokine therapies. Computational protein design now enables de novo creation of such sensors (2026 Michelson Prize research).
• Orthogonal cytokine/receptor pairs - synthetic IL-2 variants that only signal through engineered receptors expressed on adoptively transferred T cells, allowing completely localized immune activation without affecting endogenous cells
• Cytokine-armored CAR-T cells - CAR-T cells engineered to secrete specific cytokines (IL-15, IL-21, IL-18) in the tumor microenvironment to sustain themselves and recruit innate effectors

7. Nanobodies as Cytokine Antagonists

• Targets: TNF-α, IL-6, IL-17A, CXCL10, VEGF, and intracellular STAT3
• AI/ML-assisted design is accelerating discovery and affinity optimization
• Oral and nanoparticle delivery systems for cytokine-targeting nanobodies are in preclinical development
• Multiple clinical trials underway

8. Cytokine Profiling for Disease Endotyping

• In asthma: high IL-5/IL-13/IgE vs. non-T2 endotypes guide biologic choice
• In IBD: IL-23 dominant vs. TNF-dominant disease
• In sepsis: hyper-inflammatory (cytokine storm) vs. immunosuppressive phenotypes guide timing of anti-cytokine vs. immunostimulatory therapy
• In dermatology: Th2 (AD), Th17 (psoriasis), Th1/Th17 mixed (PsA) endotypes inform drug selection

Key Themes Summarized

• Cytokines in cancer: Kureshi & Dougan, Cancer Cell 2025 (PMID 39672170)
• Cytokines in IBD: Neurath, Nat Rev Immunol 2024 (PMID 38486124)
• Anti-cytokine biologics in asthma: Israel et al., Lancet 2025 (PMID 41038208)
• Nanobodies for cytokine blockade: Vijayandran et al., Int Immunopharmacol 2025 (PMID 40858048)
• Interleukins overview: StatPearls, updated Dec 2025