Immunocompetent Lung-on-a-Chip: Engineering the Pulmonary Immune Microenvironment for Disease Modeling

Lung-on-a-chip (LOC) models are increasingly used to study pulmonary disease, yet most platforms are still judged primarily by structural fidelity rather than immune function. Here, we review the emergence of immunocompetent LOCs and propose a functional grading framework to benchmark immune integration, from barrier-only models to innate immune surveillance, adaptive immune responses, and lymphoid structure reconstitution. Using this framework, we assess how engineering parameters, including materials, mechanics, fluidics, extracellular matrix, and immune cell sourcing, define the level of immunocompetence that a platform can achieve. We show that the field has progressed considerably in recapitulating innate immunity but remains stalled at the transition to antigen-specific T- and B-cell responses, because current platforms struggle to reconcile the prolonged cell–cell contacts required for adaptive priming with the continuous perfusion needed for tissue homeostasis. Overcoming this gap will demand longer-term culture stability, improved strategies for autologous multi-lineage cell sourcing, and the integration of LOCs with multi-organ immune circuits, spatial multi-omics, and AI-driven multimodal data analytics. Together, these advances are likely to define the next generation of translational pulmonary immune models.