Engineering Immune Microenvironments for Organoid-on-a-Chip Systems

Organoid-on-a-chip technology synergizes the self-organizing capacity and cellular complexity of organoids with the precise microenvironmental control offered by organ-on-a-chip systems, significantly advancing the physiological relevance of in vitro models for studying development, disease, and drug responses. However, a critical bottleneck persists: the integration and maintenance of a functional immune microenvironment, which is essential for accurately modeling complex diseases (e.g., cancers, inflammatory disorders) and therapies (e.g., immunotherapies). While recent reviews have categorized immune organoid-on-a-chip progress by organ type, this review adopts a bioengineering-centric approach to deconstruct immune microenvironment construction. We systematically analyze key parameters—including immune cell integration strategies/sourcing, target cell interactions, immune cell motility patterns, and immune network complexity—across diverse model systems. Furthermore, we critically evaluate the transformative applications of these immune-competent models in drug toxicity screening, cell therapy interactions, and gene therapy efficacy assessment. Finally, we discuss persistent challenges and future directions for achieving truly predictive human immune-competent in vitro models. This synthesis provides a methodological framework for advancing the design and application of next-generation organoid-on-a-chip platforms.