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such as inflammatory bowel diseases, where immune cells and activation could be significantly reduced, thereby
contribute to chronic inflammation and tissue damage. alleviating the inflammatory response in IIOs. The IIOs
Furthermore, these immune-competent organoids provide successfully integrated autologous tissue-resident immune
a valuable platform for exploring how pathogens affect the cells and could simulate pathological processes such as
gut, how the immune system responds to infections, and intestinal inflammation, providing a novel in vitro model
how autoimmune conditions such as celiac disease arise for studying intestinal immune responses. Inhibiting the
when the immune system mistakenly targets healthy gut Rho pathway could mitigate TRM cell-mediated intestinal
tissue. Using patient-specific cells, these models also offer inflammation, providing a theoretical basis for developing
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the potential for personalized treatment strategies tailored to new immunotherapeutic strategies.
individual immune profiles, advancing precision medicine.
Overall, gut organoids with resident immune cells provide 4. Breakthrough disease interventions with
an essential tool for studying gut immunity and disease organoids
mechanisms and for testing therapeutic interventions in a Organoids have ushered in transformative applications across
more physiologically relevant context. multiple fields, particularly in transplantation therapy and

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The intestinal mucosal immune system is the largest drug discovery. In the realm of transplantation, organoids
pool of immune cells in the human body and is responsible have shown groundbreaking potential in treating hard tissue
for maintaining homeostasis between the intestinal barrier disorders, such as regenerating bone or cartilage, where
and luminal contents. The close interaction between their ability to mimic structural and functional properties
the epithelium and the immune system is essential for of native tissues has led to significant advancements in
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maintaining tissue homeostasis, and disruptions in this regenerative medicine. These developments offer new
relationship are associated with autoimmune diseases and hope for conditions previously deemed untreatable. In
cancer. Traditional stem cell-derived organoid models are drug discovery, organoids have revolutionized high-
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primarily used to simulate epithelial cell functions but lack throughput drug screening and toxicity testing. Their
tissue-resident immune cells, thus failing to fully capture ability to closely replicate human tissue responses has
organ-level physiological and pathological processes. enhanced the accuracy of identifying effective compounds
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Using an enzyme-free, scaffold-based crawl-out protocol, while reducing false positives. AI-assisted platforms
Recaldin et al. isolated large numbers of intestinal immune integrated with organoid-based models have further
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cells, including tissue-resident memory T cells (TRM) accelerated drug screening, enabling the rapid analysis of
cells, from adult human intestinal tissues. This method large datasets to identify optimal therapeutic candidates
retains the tissue-resident characteristics of the cells. Then, with reduced side effects. In addition, organoids have been
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they developed human intestinal immuno-organoids pivotal in recognizing disease-causing factors, including
(IIOs) by co-culturing intestinal epithelial organoids with environmental toxins or pathogenic compounds, offering
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autologous TRM cells. These TRM cells integrate into the critical insights for preventative and therapeutic strategies.
epithelial layer and continuously monitor the intestinal These breakthroughs not only expand the possibilities for
barrier. Through single-cell RNA sequencing (scRNA- personalized medicine but also redefine how diseases are
seq), researchers analyzed the transcriptomes of immune treated and managed, positioning organoids as essential
and epithelial cells in IIOs, revealing differences in gene tools in modern biomedical research. 53
expression and function between TRM cells and peripheral
blood mononuclear cells (PBMCs) (Figure 7). Compared 4.1. Bone organoids for hard tissue repair
to PBMCs, TRM cells exhibited higher migratory capacity The skeleton forms a robust structure capable of bearing
and ability to integrate with epithelial cells. Within IIOs, weight and supporting the body by combining rigid
they could migrate dynamically and had elongated shapes, inorganic minerals with an organic matrix that provides
resembling the “flossing” behavior observed in mouse flexibility. Bone organoids are a distinct type of organoid
intestines. Researchers further used the IIOs to study technology focused on simulating bone tissue in vitro.
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intestinal inflammation caused by EpCAM-targeting T-cell Multiple research teams have successfully developed
bispecific antibodies (TCBs) in cancer immunotherapy. various types of bone organoids aimed at promoting bone
The results showed that IIOs could stimulate the tissue repair and regeneration. For example, a study utilized
inflammatory response observed clinically, characterized microfluidic technology to create a “bone marrow-on-a-
by TRM cell-mediated epithelial apoptosis. After TCB chip” device capable of culturing live bone marrow in vitro,
treatment, an activated CD8+ T cell population emerged recreating a functional hematopoietic microenvironment.
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in IIOs, gradually acquiring cytotoxic features. In addition, In 2021, Akiva et al. employed silk fibroin as a scaffold
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the CD4+ T cell population showed a trend of shifting material, cultivating human bone marrow mesenchymal
from cytokine secretion to cytotoxicity. By inhibiting stem cells in vitro to differentiate into functional, 3D, self-
the Rho pathway, it was found that TRM cell migration organizing osteoblasts and osteocytes, and successfully

Volume 1 Issue 2 (2025) 10 doi: 10.36922/OR025040005