WNK4 restrains endometrial cancer progression by reprogramming macrophage polarization toward an M1-like phenotype.

Authors

Jiarong He, Tian Zhang, Menglan Xiong, Jing Zhao, Ziqing Wan, Guang Li, Qi Tian, Pu Zhang, Chuqiang Shu

Published in

Molecular biology reports. Volume 53. Issue 1. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

Endometrial cancer lacks robust immune-linked biomarkers that can be translated into tractable therapeutic strategies. WNK4, a member of the with-no-lysine (WNK) kinase family, is involved in cancer-relevant signaling pathways; however, its immunological significance in endometrial cancer has yet to be defined.
Immune deconvolution and gene-immune correlation analyses were performed to relate WNK4 to immune-cell-associated signatures. WNK4 expression was assessed in clinical endometrial cancer tissues and cell lines by immunoblotting. Macrophage polarization was modeled using phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages with interleukin-4 (IL-4) induction, followed by WNK4 overexpression. Polarization status was evaluated by marker expression and flow cytometry. Conditioned macrophage states were tested in Transwell co-culture with Ishikawa and HEC-1-A cells to assess viability, clonogenicity, migration/invasion, and apoptosis. To confirm the impact on tumor growth and macrophage-marker expression within tumors, we established a nude-mouse xenograft model.
WNK4 was reduced in endometrial cancer tissues and malignant endometrial cell lines. Correlation analyses linked WNK4 to immune-state features, including an inverse association with M2-like macrophage signatures. In THP-1-derived macrophages, WNK4 overexpression counteracted IL-4-driven M2-like polarization and shifted cells toward an M1-like profile. In co-culture, WNK4-modified macrophages suppressed proliferative and motile phenotypes of endometrial cancer cells and increased apoptotic signaling. In vivo, WNK4 overexpression inhibited xenograft growth and was accompanied by macrophage-marker changes consistent with reduced M2-like features.
WNK4 acts as an immune-relevant suppressor in endometrial cancer, partly by limiting M2-like polarization and weakening macrophage-driven tumor support.

PMID:
42627588
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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