Host-Fungus Interactions Link Autoimmune and Immune-Mediated Inflammatory Diseases to Gastrointestinal Cancer: Lessons from KA/KA and Card9-/- Mouse Models.
- 1Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Abstract
Autoimmune diseases, immune-mediated inflammatory diseases, and cancer are distinct pathological conditions that can intersect through immune dysregulation, chronic inflammation, impaired host defense, and altered host-microbe interactions. In selected settings, autoimmune and immune-mediated inflammatory diseases are associated with increased gastrointestinal cancer risk. Although bacterial and viral contributions to inflammation-associated cancer have been extensively studied, the role of fungi remains less investigated. This Opinion article discusses host-fungus interactions through two experimental mouse models that connect altered immune tolerance, innate antifungal responses, and gastrointestinal tumorigenesis. Kinase-dead IKKα K44A knock-in mice develop defective central immune tolerance, APECED-like autoimmune manifestations, mucosal fungal infection, epithelial EGFR signaling, and esophageal squamous cell carcinoma. By contrast, Card9-/- mice provide a distinct model in which impaired innate antifungal immunity alters intestinal fungal ecology and myeloid-cell responses in colitis-associated colorectal cancer. In the CARD9 setting, fungi may exert pathogenic or protective effects depending on host genotype, immune context, fungal species, and mycobiome structure. Together, these models provide useful tools for investigating how fungi may contribute to gastrointestinal tumorigenesis through cancer-promoting inflammation and immune suppression in a context-dependent manner. However, these findings do not yet validate clinical strategies and should not be interpreted as broadly representative of all autoimmune or immune-mediated inflammatory diseases. Further mechanistic and human studies are needed.
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BibTeX
@article{zhu2026hostfungus,
title = {{Host-Fungus Interactions Link Autoimmune and Immune-Mediated Inflammatory Diseases to Gastrointestinal Cancer: Lessons from KA/KA and Card9-/- Mouse Models.}},
author = {Joyce Zhu and Diya Rawal and Adeline Cheng and Debra Tross and Xin Li and Teizo Yoshimura and Keqiang Chen and Yinling Hu and Feng Zhu},
journal = {Biology},
year = {2026},
month = oct,
doi = {10.3390/biology15201878},
url = {https://europepmc.org/article/MED/42939479},
note = {CC BY},
}
RIS
TY - JOUR
TI - Host-Fungus Interactions Link Autoimmune and Immune-Mediated Inflammatory Diseases to Gastrointestinal Cancer: Lessons from KA/KA and Card9-/- Mouse Models.
AU - Joyce Zhu
AU - Diya Rawal
AU - Adeline Cheng
AU - Debra Tross
AU - Xin Li
AU - Teizo Yoshimura
AU - Keqiang Chen
AU - Yinling Hu
AU - Feng Zhu
PY - 2026
DA - 2026/10/18
JO - Biology
DO - 10.3390/biology15201878
UR - https://europepmc.org/article/MED/42939479
AB - Autoimmune diseases, immune-mediated inflammatory diseases, and cancer are distinct pathological conditions that can intersect through immune dysregulation, chronic inflammation, impaired host defense, and altered host-microbe interactions. In selected settings, autoimmune and immune-mediated inflammatory diseases are associated with increased gastrointestinal cancer risk. Although bacterial and viral contributions to inflammation-associated cancer have been extensively studied, the role of fungi remains less investigated. This Opinion article discusses host-fungus interactions through two experimental mouse models that connect altered immune tolerance, innate antifungal responses, and gastrointestinal tumorigenesis. Kinase-dead IKKα K44A knock-in mice develop defective central immune tolerance, APECED-like autoimmune manifestations, mucosal fungal infection, epithelial EGFR signaling, and esophageal squamous cell carcinoma. By contrast, Card9-/- mice provide a distinct model in which impaired innate antifungal immunity alters intestinal fungal ecology and myeloid-cell responses in colitis-associated colorectal cancer. In the CARD9 setting, fungi may exert pathogenic or protective effects depending on host genotype, immune context, fungal species, and mycobiome structure. Together, these models provide useful tools for investigating how fungi may contribute to gastrointestinal tumorigenesis through cancer-promoting inflammation and immune suppression in a context-dependent manner. However, these findings do not yet validate clinical strategies and should not be interpreted as broadly representative of all autoimmune or immune-mediated inflammatory diseases. Further mechanistic and human studies are needed.
SN - 2079-7737
ER -