Hypoxia tumor-associated macrophages facilitate hepatocellular carcinoma metastasis via uPA-uPAR pathway.

Authors

Yijun Wang, Xiaomin You, Xiangyuan Luo, Wenjie Huang, Zerui Zhang, Limin Xia

Published in

Journal of translational medicine. Jul 18, 2026. Epub Jul 18, 2026.

Abstract

Hepatocellular carcinoma (HCC) arises within a hypoxic and immunosuppressive tumor microenvironment (TME), where tumor-associated macrophages (TAMs) constitute a major immune population. The impact of hypoxia on TAM functional heterogeneity and their contribution to HCC growth and metastasis remain incompletely understood.
We integrated multiple single-cell RNA sequencing datasets and developed a machine learning framework to map cellular hypoxia at single-cell resolution. Hypoxic TAMs (H-TAM) were characterized using transcriptomic and functional assays, including pseudotime trajectory analysis, regulatory network inference, in vitro co-culture, and orthotopic mouse models. Drug sensitivity correlations and in vivo validation were performed to evaluate therapeutic strategies.
H-TAM represented the most hypoxic immune population in HCC and exhibited enhanced interactions with malignant hepatocytes. Transcriptomic profiling revealed HIF-1α-dependent hypoxia signaling and upregulation of plasminogen activator, urokinase (uPA, encoded by PLAU). H-TAM-derived uPA engaged its receptor uPAR on HCC cells, promoting epithelial-mesenchymal transition (EMT), migration, invasion, and lung metastasis. In line with this, genetic silencing of the corresponding mouse gene Plau in hypoxia-exposed bone marrow-derived macrophages (H-BMDM) markedly attenuated these pro-tumorigenic effects. Integrative drug sensitivity analysis identified dasatinib as a potential therapeutic agent in HCC with high uPAR expression, and in vivo administration selectively suppressed H-BMDM mediated tumor progression and metastasis while prolonging mouse survival.
Hypoxia drives TAM heterogeneity in HCC via an H‑TAM‑intrinsic HIF‑1α-uPA axis that engages uPAR on HCC cells to promote metastasis. uPAR is a potential prognostic biomarker, and dasatinib is a promising therapy to block this axis and improve outcomes.

PMID:
42471734
Bibliographic data and abstract were imported from PubMed on 19 Jul 2026.

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