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image of Foxp3+ Tregs Promote M2 Macrophage Polarization via Sirt1-ERK1/2-STAT3 Pathway in Ovarian Cancer Progression

Abstract

Introduction

Epithelial Ovarian Cancer (EOC) is a highly aggressive gynecological malignancy with a high mortality rate primarily due to late-stage diagnosis and metastatic dissemination. Regulatory T cells (Tregs) have emerged as critical mediators of immune evasion, yet the role of Foxp3+ Tregs in modulating Tumor-Associated Macrophage (TAM) polarization and the underlying molecular mechanisms in EOC remains unclear.

Methods

An orthotopic EOC mouse model and co-culture systems were employed to investigate the effects of Foxp3+ Tregs on TAM polarization. Quantitative Real-Time PCR (qRT-PCR), flow cytometry, Western blotting, wound healing, and transwell assays were performed to assess gene expression, immune cell infiltration, and tumor cell migration/invasion. Foxp3 knockdown was achieved using Adeno-Associated Virus (AAV)-mediated delivery to evaluate its effects .

Results

Foxp3+ Tregs induced macrophage polarization toward the M2 phenotype, characterized by downregulation of M1 markers (IL-1β, iNOS) and upregulation of M2 markers (IL-10, Arg-1). Mechanistically, Foxp3+ Tregs activated the Sirt1-ERK1/2-STAT3 signaling pathway while suppressing NF-κB activity. , Foxp3+ Tregs enhanced the migratory and invasive capacities of ovarian cancer cells, whereas Foxp3 knockdown significantly reduced tumor growth and M2 macrophage infiltration.

Discussion

These findings suggest that Foxp3+ Tregs play a pivotal role in shaping the immunosuppressive tumor microenvironment in EOC by promoting M2 macrophage polarization through Sirt1-ERK1/2-STAT3 signaling and NF-κB suppression, ultimately facilitating tumor progression.

Conclusion

Foxp3+ Tregs drive immunosuppressive macrophage polarization and ovarian cancer progression, highlighting Foxp3 as a potential therapeutic target for EOC treatment.

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2025-10-29
2025-12-14

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Foxp3+ Tregs Promote M2 Macrophage Polarization via Sirt1-ERK1/2-STAT3 Pathway in Ovarian Cancer Progression
Bentham Science Publishers ; https://doi.org/10.2174/0115665232417125251021114250
/content/journals/cgt/10.2174/0115665232417125251021114250
/content/journals/cgt/10.2174/0115665232417125251021114250
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  • Article Type:     Research Article
Keywords: tregs ; Ovarian cancer ; Foxp3 ; Sirt1-ERK1/2-STAT3 ; immunosuppressive macrophage ; macrophages

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