Immune Microphysiological Systems for Human Innate Immunity

ABSTRACT Reconstituting human immune function in vitro remains challenging due to the spatial organization, dynamic signaling, and multicellular coordination underlying immune responses. Immune microphysiological systems (iMPS) address limitations of conventional 2D cultures, organoids, and animal models by integrating human‐derived cells within microengineered environments that recapitulate tissue‐specific immune microenvironments. This review outlines the cellular, structural, and functional requirements for designing immune‐competent microphysiological systems (MPS). We describe design strategies enabling spatiotemporal control of cell positioning, fluid flow, chemokine gradients, and matrix mechanics, and discuss material considerations influencing immune cell survival, migration, and polarization. We further summarize applications of iMPS across key innate immune populations, including natural killer cells, dendritic cells, and macrophages, with emphasis on cytotoxic, antigen sampling, chemotaxis, and tumor–immune interactions. Finally, we discuss future directions including multi‐organ immune modeling, integration of patient‐derived cells, and standardization to support translational research and therapeutic development.