Clinical bottom line
Emerging therapies targeting innate lymphoid cells (ILCs) represent a novel immunomodulatory approach in autoimmune diseases, with early-phase clinical trials and preclinical studies suggesting potential benefits in conditions such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. However, current evidence remains preliminary, with limited large-scale, randomized controlled trials to definitively establish efficacy and safety. Clinicians should consider these therapies as investigational and monitor ongoing research for future integration into practice.
What the evidence shows
Innate lymphoid cells, a heterogeneous group of immune cells lacking antigen-specific receptors, contribute to tissue homeostasis and inflammation. Dysregulation of ILC subsets (notably ILC1, ILC2, and ILC3) has been implicated in the pathogenesis of several autoimmune diseases through cytokine production and interaction with adaptive immunity (Spits et al., 2016). Targeting ILCs aims to modulate these pathogenic pathways.
Recent systematic reviews and early-phase clinical trials have evaluated agents modulating ILC activity:
- **ILC2-targeted therapies:** Biologics modulating IL-33 and IL-25 pathways, which activate ILC2s, have shown promise in reducing type 2 inflammation in autoimmune contexts such as eosinophilic esophagitis and atopic dermatitis (Kim et al., 2021). However, their role in systemic autoimmunity remains under investigation.
- **ILC3 modulation:** Given the role of ILC3s in mucosal immunity and their dysregulation in inflammatory bowel disease (IBD), therapies targeting IL-23/IL-17 axis indirectly affect ILC3 function. Ustekinumab and risankizumab, IL-23 inhibitors approved for Crohn’s disease and psoriasis, may exert part of their effect via ILC3 modulation (Sandborn et al., 2019; Feagan et al., 2017).
- **ILC1 and NK cell-targeted approaches:** Agents modulating IFN-γ-producing ILC1 and NK cells are under early preclinical evaluation for diseases like systemic lupus erythematosus (SLE), where aberrant type 1 immunity contributes to pathology (Wang et al., 2020).
Overall, these therapies are in early clinical development stages, with some phase 2 trials reporting modest clinical improvements and acceptable safety profiles. However, heterogeneity in patient populations, endpoints, and ILC-targeting specificity limits broad conclusions.
Caveats and uncertainty
- **Limited clinical trial data:** Most evidence derives from small, early-phase studies or extrapolation from biologics targeting cytokines that influence ILCs indirectly. Direct ILC-targeted agents are largely investigational.
- **Heterogeneity of ILC subsets:** The diverse roles of ILC subsets in different tissues and diseases complicate targeting strategies. Suppressing one subset may inadvertently impair protective immunity or exacerbate other immune pathways.
- **Biomarker challenges:** Reliable biomarkers for ILC activity and patient stratification are lacking, limiting personalized therapy approaches.
- **Long-term safety unknown:** Given the role of ILCs in tissue repair and host defense, long-term immunosuppression risks remain to be fully characterized.
- **Disease-specific effects:** The impact of ILC modulation may vary significantly between autoimmune diseases, requiring disease-specific validation.
How this may change practice
At present, therapies directly targeting innate lymphoid cells should be considered experimental and primarily accessed through clinical trials. Clinicians managing autoimmune diseases should:
- Stay informed on emerging data from ongoing trials evaluating ILC-targeted agents.
- Consider the potential of ILC modulation as part of future precision immunotherapy, especially for patients refractory to conventional biologics.
- Recognize that current approved therapies targeting cytokines influencing ILCs (e.g., IL-23 inhibitors) may exert part of their benefit via ILC pathways, informing mechanistic understanding and off-label considerations.
- Advocate for biomarker development to enable patient selection and monitoring in future ILC-targeted therapy use.
Integration of ILC-targeted therapies into routine clinical practice awaits robust phase 3 trial data confirming efficacy and safety.