From Single Cytokines to Networks: A Systems Immunology View of Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic immune-mediated disorder of the gastrointestinal tract underpinned by dysregulated mucosal immune responses. Although biological therapies targeting individual cytokines have improved clinical outcomes, most patients fail to achieve durable remission, highlighting the limitations of single-target approaches. Emerging evidence suggests that cytokines function not in isolation but within highly interconnected signaling networks. Systems-level analyses using single-cell transcriptomics and network-based reconstruction reveal that UC phenotypes are characterized by specific rewiring of cytokine communication. Longitudinal multi-omics data, ex vivo perturbation models, and spatial transcriptomics offer opportunities to extend this framework by resolving the spatiotemporal dynamics of cytokine communication across disease states. Integration with systems genomics and microbial-metabolic networks could further refine patient-specific cytokine models. Together, this multi-layered framework supports a paradigm shift away from reductionist, single-cytokine approaches toward a dynamic, spatially organized, and genetically constrained systems immunology perspective of mucosal inflammation, informing novel precision medicine strategies.