Breathing immunity into in vitro lung models.

BACKGROUND: The human lung hosts a highly specialised immune microenvironment responsible for defence, repair and responses to pathogens and environmental insults. Animal models insufficiently recapitulate human-specific immune pathways, limiting translational insight into both acute and chronic respiratory diseases. Advances in organoids, organ-on-chip technologies and biofabrication have enabled increasingly realistic in vitro lung models; however, many systems still lack immune components and the complexity required to capture dynamic host-immune interactions. CONTENT: This review outlines the existing impact of immune-competent lung models on clinical drug development and disease mechanistic studies, as well as the future potential and the technical challenges with integrating immune cells into in vitro lung models that need to be overcome to maximise clinical relevance. We discuss major bottlenecks and corresponding potential solutions, including immune cell viability and phenotype maintenance, microenvironmental compatibility, recruitment dynamics and the reproducibility-complexity trade-off. We further explore how cutting-edge biofabrication approaches, including tunable extracellular matrices, bioprinting and engineered microvascular networks, enable physiologically relevant interactions between immune and resident lung cell populations. CONCLUSION: Collectively, these advances pave the way for improved immune-competent lung models to accelerate therapeutic discovery and enhance model translational relevance.