Dihydroartemisinin Promotes N1 Polarization of Tumor-Associated Neutrophils and Enhances Their Anti-Tumor Activity via Hub Gene Modulation

TL;DR

This study shows that dihydroartemisinin (DHA) can shift tumor-associated neutrophils toward an anti-tumor state, potentially improving cancer treatment.

Contribution

The paper identifies DHA as a novel agent that modulates tumor-associated neutrophil polarization through specific hub gene regulation.

Findings

DHA promotes N1 polarization of neutrophil-like cells by upregulating anti-tumor markers like TNF and IL1B.

DHA-treated cells show enhanced cytotoxic activity against hepatocellular carcinoma cells.

Molecular docking suggests DHA interacts with key hub proteins involved in TAN polarization.

Abstract

Background: Tumor-associated neutrophils (TANs) exhibit remarkable functional plasticity within tumor microenvironment (TME), with N1-like subtypes promoting anti-tumor immunity and N2-like subtypes facilitating tumor progression. Despite their critical role in cancer immunology, strategies to selectively modulate TAN polarization remain limited. Methods: We integrated transcriptomic analyses of TAN subtypes to identify potential hub molecules. Molecular docking and experimental assays were used to evaluate DHA’s effect on neutrophil-like cell polarization. Results: Hub genes (TNF, IL1B, PTGS2, BCL2A1, MSR1, ACOD1, CXCL16, CLEC10A, and SOCS3) were identified, with TNF serving as a potential core regulator. Molecular docking indicated that DHA forms stable interactions hub proteins. Experimentally, DHA treatment of neutrophil-like dNB4 cells promoted N1 polarization, evidenced by upregulation of TNF, IL1B, PTGS2, BCL2A1, MSR1, ACOD1, CXCL16, and N1 markers PD-L1 and NOX2, and downregulation of N2 marker CEACAM8 and hub genes CLEC10A and SOCS3. Functional assays demonstrated that DHA-treated cells exhibited increased secretion of TNF, IL1β, ROS, and PD-L1, accompanied by enhanced cytotoxic activity against hepatocellular carcinoma cells in a co-culture system. Conclusions: These findings reveal the molecular mechanisms underlying TAN polarization, and establish DHA as a potent immunomodulatory agent capable of reshaping TANs toward an anti-tumor phenotype.

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