Work

MAGI3 Acts as an Intestinal Epithelial Gatekeeper in Inflammation‐Associated Colorectal Cancer by Suppressing the STAT3‐CCL2 Axis and TAM‐Mediated Immunosuppression

Year: 2026

Type: article

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.

Source: Advanced Science

DOI: 10.1002/advs.78577