Antiviral immune responses in human organoid models of emerging viral infections: A systematic review

Human organoid models have emerged as powerful tools for studying viral pathogenesis and host immune responses in physiologically relevant human tissues. These three-dimensional systems provide opportunities to investigate virus–host interactions that are difficult to replicate in traditional cell culture models. However, a comprehensive synthesis of antiviral immune responses across different organoid systems and viral families remains limited. A systematic review was conducted in accordance with PRISMA guidelines to evaluate studies investigating antiviral immune responses in human organoid models. Literature searches were performed across major scientific databases for studies published between 2010- January 2026. After removal of duplicates and screening of titles, abstracts, and full texts based on predefined inclusion criteria, 23 studies were included in the final qualitative synthesis. Data were extracted on organoid origin, virus type, immune signaling pathways, and reported immune responses. The included studies investigated viruses from seven families, including Coronaviridae , Flaviviridae , Orthomyxoviridae , Picornaviridae , Filoviridae , Poxviridae , and Togaviridae . Organoid models primarily represented neural, respiratory, intestinal, and hepatic tissues derived from human embryonic stem cells, induced pluripotent stem cells, or adult stem cells. Across studies, viral infection commonly activated innate immune pathways involving pattern-recognition receptors such as Toll-like receptors and RIG-I–like receptors, leading to downstream activation of NF-κB and interferon regulatory factor signaling. These pathways induced production of type I and type III interferons, interferon-stimulated genes, and pro-inflammatory cytokines including IL-6, TNF-α, CXCL10, and CCL5. While several viruses triggered strong interferon-mediated antiviral responses, others demonstrated attenuated immune activation, suggesting virus-specific mechanisms of immune modulation or evasion. Human organoid models provide physiologically relevant platforms for studying antiviral immune responses across diverse viral infections and tissue types. The evidence highlights conserved innate immune pathways alongside virus- and tissue-specific differences in immune activation. These systems hold significant potential for advancing our understanding of viral pathogenesis, immune regulation, and therapeutic development.