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High-potassium microenvironment drives KCNMA1⁺ CAF-mediated progression of perineural invasion-positive colorectal cancer via the CCL11/CCR5 axis

ABSTRACT: Perineural invasion (PNI) is an established independent prognostic risk factor in colorectal cancer (CRC) and is significantly associated with resistance to immunotherapy; however, the mechanisms underlying cellular communication remain inadequately understood. Here, using single-nucleus RNA sequencing, we identified a previously uncharacterized KCNMA1⁺ cancer-associated fibroblast (CAF) subpopulation specifically enriched in PNI-positive CRC. Analysis of multicenter clinical cohorts confirmed that KCNMA1⁺CAFs correlate with PNI status and poor survival. Functionally, this subset of CAFs induces pro-tumor M2-type macrophage polarization via paracrine CCL11, thereby remodeling the immunosuppressive tumor microenvironment and facilitating tumor progression. In terms of the induction mechanism, tumor infiltration into neural tissues induces extensive cellular necrosis within the PNI niche, creating a potassium-rich (K+-rich) microenvironment that drives the phenotypic transition of CAFs toward the KCNMA1⁺ subtype. Pharmacological inhibition of the CCL11-CCR5 axis effectively attenuates KCNMA1⁺CAF-mediated immunosuppression and sensitizes PNI-positive tumors to anti-PD-1 therapy. Collectively, this study elucidates the critical role of PNI-induced ionic microenvironment remodeling in promoting CAF heterogeneity and suggests potential combination therapeutic strategies for patients with PNI-positive CRC.

ORGANISM(S): Homo Sapiens

SUBMITTER: Zhangfa Song

PROVIDER: PXD077367 | iProX | Mon Apr 20 00:00:00 BST 2026

REPOSITORIES: iProX

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