MAGI3 Acts as an Intestinal Epithelial Gatekeeper in Inflammation‐Associated Colorectal Cancer by Suppressing the STAT3‐CCL2 Axis and TAM‐Mediated Immunosuppression
5 affiliations
- 1Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Capital Medical University Beijing China
- 2Laboratory For Clinical Medicine Capital Medical University Beijing China
- 3Department of General Surgery State Key Lab of Digestive Health Beijing Friendship Hospital Capital Medical University National Clinical Research Center for Digestive Diseases Beijing China
- 4Department of Medical Oncology Beijing Tuberculosis and Thoracic Tumor Research Institute Beijing Chest Hospital Capital Medical University Beijing China
- 5Beijing Obstetrics and Gynecology Hospital Capital Medical University Beijing Maternal and Child Health Care Hospital Beijing China
Abstract
Chronic intestinal inflammation is a major driver of colorectal cancer (CRC). As the mucosal barrier's frontline sentinel, the intestinal epithelium initiates the inflammation‐to‐cancer transition. However, the early cell‐intrinsic events that convert inflammatory responses into a sustained pro‐tumorigenic program remain unclear. In this study, we identify MAGI3 as an intestinal epithelial guardian progressively lost during inflammation‐associated colorectal tumorigenesis. Low MAGI3 correlates with heightened inflammatory activity and poor prognosis. Inflammation‐induced epithelial MAGI3 downregulation drives STAT3 hyperactivation, CCL2 upregulation, and recruitment of M2‐like tumor‐associated macrophages (TAMs), thereby promoting an immunosuppressive microenvironment and tumor progression. By contrast, single‐cell RNA sequencing (scRNA‐seq) demonstrated that MAGI3 overexpression reshapes the composition of TAMs and limits M2‐like TAM infiltration. Mechanistically, the PDZ1 domain of MAGI3 binds directly to the C‐terminus of STAT3, blocking the SH2 pocket, impairing the interaction between STAT3 and IL‐6R/JAK2, and ultimately inhibiting STAT3 phosphorylation at Tyr705. Clinically, the MAGI3‐STAT3 axis offers a new therapeutic strategy for chemotherapy‐resistant CRC, with low MAGI3 expression predicting enhanced sensitivity to STAT3 inhibitors. Collectively, these findings establish MAGI3 as a gatekeeper of the intestinal epithelium in inflammation‐associated CRC, with the MAGI3‐STAT3 axis regulating TAM recruitment. Targeting the MAGI3‐STAT3 axis could offer an early intervention to reverse inflammation‐to‐cancer transition.
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BibTeX
@article{yang2026magi3,
title = {{MAGI3 Acts as an Intestinal Epithelial Gatekeeper in Inflammation‐Associated Colorectal Cancer by Suppressing the STAT3‐CCL2 Axis and TAM‐Mediated Immunosuppression}},
author = {Yumeng Yang and Zhigang Bai and Haibo Wang and Yu Guo and Yan Zhang and Meihan Hu and Shuaikang Fan and Ran Song and Tongmei Zhang and Mengqi Deng and Xiaomei Yang and Zhongtao Zhang and Junqi He},
journal = {Advanced Science},
year = {2026},
month = oct,
doi = {10.1002/advs.78577},
url = {https://doi.org/10.1002/advs.78577},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - MAGI3 Acts as an Intestinal Epithelial Gatekeeper in Inflammation‐Associated Colorectal Cancer by Suppressing the STAT3‐CCL2 Axis and TAM‐Mediated Immunosuppression
AU - Yumeng Yang
AU - Zhigang Bai
AU - Haibo Wang
AU - Yu Guo
AU - Yan Zhang
AU - Meihan Hu
AU - Shuaikang Fan
AU - Ran Song
AU - Tongmei Zhang
AU - Mengqi Deng
AU - Xiaomei Yang
AU - Zhongtao Zhang
AU - Junqi He
PY - 2026
DA - 2026/10/31
JO - Advanced Science
DO - 10.1002/advs.78577
UR - https://doi.org/10.1002/advs.78577
AB - Chronic intestinal inflammation is a major driver of colorectal cancer (CRC). As the mucosal barrier's frontline sentinel, the intestinal epithelium initiates the inflammation‐to‐cancer transition. However, the early cell‐intrinsic events that convert inflammatory responses into a sustained pro‐tumorigenic program remain unclear. In this study, we identify MAGI3 as an intestinal epithelial guardian progressively lost during inflammation‐associated colorectal tumorigenesis. Low MAGI3 correlates with heightened inflammatory activity and poor prognosis. Inflammation‐induced epithelial MAGI3 downregulation drives STAT3 hyperactivation, CCL2 upregulation, and recruitment of M2‐like tumor‐associated macrophages (TAMs), thereby promoting an immunosuppressive microenvironment and tumor progression. By contrast, single‐cell RNA sequencing (scRNA‐seq) demonstrated that MAGI3 overexpression reshapes the composition of TAMs and limits M2‐like TAM infiltration. Mechanistically, the PDZ1 domain of MAGI3 binds directly to the C‐terminus of STAT3, blocking the SH2 pocket, impairing the interaction between STAT3 and IL‐6R/JAK2, and ultimately inhibiting STAT3 phosphorylation at Tyr705. Clinically, the MAGI3‐STAT3 axis offers a new therapeutic strategy for chemotherapy‐resistant CRC, with low MAGI3 expression predicting enhanced sensitivity to STAT3 inhibitors. Collectively, these findings establish MAGI3 as a gatekeeper of the intestinal epithelium in inflammation‐associated CRC, with the MAGI3‐STAT3 axis regulating TAM recruitment. Targeting the MAGI3‐STAT3 axis could offer an early intervention to reverse inflammation‐to‐cancer transition.
SN - 2198-3844
ER -