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ECM1/SQSTM1 Axis Remodels Colorectal Cancer Immune Microenvironment via CXCL1-CXCR2-Dependent Neutrophil Recruitment and NETosis

ABSTRACT: In this study, we demonstrate that ECM1 derived from intestinal epithelial cells (IECs) serves as a critical driver of CRC progression. The deficiency of Ecm1 specifically in intestinal epithelial significantly suppresses both colitis-associated and spontaneous colorectal tumorigenesis in vivo. Through single-cell and spatial transcriptomic analyses, we reveal that ECM1 regulates neutrophil recruitment and activation within the tumor microenvironment (TME). Mechanistically, ECM1 functions as a scaffold protein that facilitates the interaction between SQSTM1 and RIP1, thereby initiating NF-κB-meditated CXCL1 secretion. This signaling pathway recruits neutrophils and induces the formation of neutrophils extracellular traps (NETs), creating an immune barrier that excludes CD8+ T cells. Notably, targeting ECM1 effectively mitigates neutrophil-mediated immunosuppression and reverses anti-PD-1 immunotherapy resistance in subcutaneous tumor-bearing mice.

ORGANISM(S): Homo Sapiens

SUBMITTER: Debing Xiang

PROVIDER: PXD079113 | iProX | Mon Jun 01 00:00:00 BST 2026

REPOSITORIES: iProX

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