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

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.