An integrated cell atlas of the innate lymphoid cells in health and disease 2254590

Introduction Innate lymphoid cells (ILCs) represent a highly diverse family of lymphocytes that play pivotal roles in tissue homeostasis, inflammation, and cancer immunity. Despite growing evidence of their plasticity and functional heterogeneity, a comprehensive understanding of human ILC diversity across pathological contexts remains limited. Methods We performed large-scale single-cell RNA sequencing (scRNA-seq) analysis of 3,322 human samples spanning 60 physiological and pathological conditions. Results By integrating and harmonizing ILC transcriptomes across tissues and diseases, we systematically characterized the cellular states, transcriptional regulators, and disease-specific adaptations of ILC subsets. Our atlas reveals both conserved and disease-specific transcriptional programs of ILCs. Pathological conditions induce profound compositional and phenotypic shifts in ILC subsets. Comparative analyses between TCF7+ ILC1 and ZNF683+ NK-derived IFNG+ ILC1 populations highlight distinct transcription factor dependencies and microenvironmental stimuli shaping their effector programs. Notably, GZMB+ ILC2 cells, enriched in multiple cancer types, were associated with improved patient prognosis, suggesting a potential cytotoxic role. In contrast, NR4A1+ ILC3 cells within NCR⁻ ILC3 clusters were preferentially enriched in tumors and inflammatory diseases, correlating with poor prognosis and resistance to immunotherapy. Conclusion This comprehensive single-cell atlas delineates the dynamic landscape of human ILCs across diseases.