Spatiotemporal heterogeneity of immune cells in knee osteoarthritis: Cytokine actions and targeted therapies.

Knee osteoarthritis (KOA) is a whole-joint disease involving the synovium, articular cartilage, subchondral bone, and infrapatellar fat pad. Immune responses contribute to its onset and progression. As immune cell composition and functional states change across disease stages and tissue environments, cytokine sources, activity, and effects also vary over time and among tissues. Most studies have examined individual immune cell types, cytokines, or joint tissues in isolation, limiting their ability to explain the diversity of KOA clinical phenotypes and the variable outcomes of cytokine-targeted treatment. This review examines the spatiotemporal heterogeneity of immune cells in KOA. It traces immune susceptibility and early activation, persistent inflammation and disease progression, and late-stage immune remodeling. It also compares immune microenvironments and cytokine effects in the synovium, articular cartilage, subchondral bone, and infrapatellar fat pad. The review then evaluates IL-1, TNF, IL-6, oncostatin M, colony-stimulating factors, and chemokines as therapeutic targets, considering their roles at different stages, the patients most likely to benefit, and the supporting treatment evidence. Emerging strategies, including modulation of immune cell recruitment and cytokine maturation, sustained local delivery, and gene therapy, are also discussed. Current evidence suggests that the effects of a given cytokine depend in part on its cellular source, the responding tissue, and the disease stage. These differences may help explain why inflammation, structural damage, and pain do not always progress together in KOA. Future studies should combine longitudinal sampling, analysis of multiple joint tissues, and single-cell and spatial omics to identify the predominant immune states in different patients and guide the selection of therapeutic targets, delivery methods, and treatment timing.