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FPR3 sustains the immunosuppression of tumor-associated macrophages and accelerates the progression of gastric adenocarcinoma

Oncogene (2025)Cite this article

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Abstract

Tumor-associated macrophages (TAMs) play a critical role in promoting tumor progression and represent a promising target for immunotherapeutic intervention. However, the phenotypic characteristics and polarization dynamics of TAMs remain poorly understood, largely due to the complex cellular heterogeneity within the tumor microenvironment. In this study, we comprehensively characterize the heterogeneity of TAMs in gastric adenocarcinoma (GA), with a particular focus on immunosuppressive subsets. Our findings demonstrate that TAMs undergo multidirectional differentiation and exhibit diverse immunoregulatory functions. Among them, FPR3⁺ macrophages are identified as a distinct immunosuppressive population associated with poor patient prognosis. Functional assays using shRNA-mediated knockdown and specific agonists reveal that FPR3 regulates macrophage proliferation and polarization and is essential for TAM formation and maintenance. Mechanistically, FPR3 upregulates FZD7 and CCDC88C, leading to activation of the intracellular Wnt/PCP pathway and downstream JNK signaling, thereby promoting TAM development. Collectively, our study identifies FPR3 as a novel marker of immunosuppressive TAMs, elucidates its mechanistic role in macrophage plasticity, and offers new insights into potential therapeutic strategies for targeting the tumor microenvironment in GA.

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Fig. 1: Single cell RNA sequencing identifies heterogeneity of tumor-associated macrophage in gastric adenocarcinoma (GA).
Fig. 2: FPR3+ macrophage polarity defines an immunosuppressive subgroup associated with poor prognosis.
Fig. 3: FPR3 regulates macrophage proliferation and polarization.
Fig. 4: FPR3 in macrophages is associated with reduced tumor progression.
Fig. 5: The deficiency of FPR3 in macrophages reduces their tumor-promoting and angiogenic functions in vivo.
Fig. 6: Knockdown of FPR3 regulates macrophage polarization by impairing the intracellular noncanonical Wnt/JNK signaling pathway.

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Data availability

All data generated in this study are freely available without any restrictions. The raw single cell RNA sequencing data of GA samples have been uploaded to GEO dataset (GSE264203). The bulk RNA-seq raw data of macrophages have been deposited in the Sequence Read Archive (SRA) database (PRJNA1165156). All other data supporting the findings of this research are provided within the article and its supplementary materials. The external raw data that support the findings were obtained from Gene Expression Omnibus (GEO) at GSE183904, GSE15459 and TCGA STAD project (https://gdc.cancer.gov).

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Acknowledgements

We express gratitude to all members of the Pathophysiology Department at Anhui Medical University for their valuable comments and advice. Additionally, we acknowledge the Center for Scientific Research at Anhui Medical University for their invaluable support in conducting our experiments. We thank OE Biotech Co., Ltd (Shanghai, China) for providing single-cell RNA-seq and assistance with bioinformatics analysis.

Funding

This work was supported by the National Natural Science Foundation of China (reference numbers 82173004, 81870085,81670097), Chinese Scholarship Council Research Collaboration Project, Grants for Scientific Research Enhancement of Anhui Medical University (2019xkjT004 and XJ2020019), Grants for Collaborative Innovation Project of Colleges and Universities in Anhui Province (GXXT-2021-063), Anhui Medical University Basic and Clinical Cooperation Project (2022xkjT029), Natural Science Foundation of Anhui Province Education Department (2022AH051183), Postgraduate Innovation Research and Practice Program of Anhui Medical University (YJS20230101, YJS20230144).

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Author notes

  1. These authors contributed equally: Minqiong Sun, Zhenya Tan, Keqiong Lin.

Authors and Affiliations

  1. Department of Pathophysiology, Anhui Medical University, Hefei, China

    Minqiong Sun, Zhenya Tan, Keqiong Lin, Zhiling Chang, Zhi Yang, Xue Yang, Gu Tang, Yakun Liu, Jicheng Zhu, Chen Kan & Hong Zheng

  2. Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Chun Li & Chunwei Peng

  3. Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China

    Hong Zheng

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Contributions

All coauthors have contributed to this study. MS, ZT, and KL conducted the experiments, analyzed data, and wrote this paper. JZ and YL were responsible for biopsies collection and data collection. ZC and ZY interpretated scRNA-seq data. ZC, ZY, XY, GT, and CL were responsible for biological experiments and manuscript revision. HZ, CP, and CK were responsible for experimental design, data interpretation, and manuscript revision.

Corresponding authors

Correspondence to Chen Kan, Chunwei Peng or Hong Zheng.

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The authors declare no competing interests.

Ethics

All studies and methods were conducted in accordance with the regulations and guidelines approved by the Ethics Committee of Anhui Medical University. The study received approval from the ethics committee of Anhui Medical University (LLSC20210872). Written informed consent was obtained from all study participants. All the animal experiments of this study were approved by the Animal Care and Use Committees at Anhui Medical University (LLSC20210972).

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Sun, M., Tan, Z., Lin, K. et al. FPR3 sustains the immunosuppression of tumor-associated macrophages and accelerates the progression of gastric adenocarcinoma. Oncogene (2025). https://doi.org/10.1038/s41388-025-03578-8

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