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Cellular and Molecular Biology

GDP-bound Rab37 modulates M2-like tumor-associated macrophage polarization by attenuating STAT1 translocation to downregulate the type I IFN pathway

British Journal of Cancer volume 132, pages 622–634 (2025)Cite this article

Subjects

Abstract

Background

Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) primarily polarize into the M2-phenotype. Our previous study showed that the small GTPase Rab37 mediates IL-6 trafficking in macrophages for M2 polarization. Here, we uncover an unconventional role of Rab37, independent of vesicle trafficking, in promoting M2 polarization of TAMs.

Methods

The gene profiles in wild-type and Rab37 knockout (KO) bone marrow-derived macrophages (BMDMs) were analyzed using cDNA microarray. The mechanism of Rab37 in regulating the interferon (IFN) pathway was confirmed through in vitro/vivo assays and clinical studies.

Results

Type I IFN signaling was highly enriched in BMDMs from Rab37 KO mice. Moreover, Rab37 induction and decreased type I IFN genes were observed in macrophages treated with lung cancer-conditioned medium and epigenetic drugs, indicating an epigenetic regulation of Rab37 in TAMs. Mechanistically, GDP-bound Rab37 interacted with the nuclear localization sequence of STAT1 to sequest it in the cytosol from its transcription activities, thus leading to the downregulation of IFN genes. Clinically, CD163+/Rab37+/STAT1cytosol in TAMs expression signature correlated with advanced tumor stages and poor survival of lung cancer patients.

Conclusions

Our findings highlight the cytosolic interaction of Rab37-STAT1 in M2 TAM polarization, with CD163+/Rab37+/STAT1cytosol TAMs as a lung cancer prognosis biomarker.

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Fig. 1: cDNA microarray and pathway analyses revealed upregulation of type I IFN signaling pathway in Rab37 KO BMDMs.
Fig. 2: Treatment with epigenetic inhibitor or cancer cell media upregulated Rab37 expression in macrophages, leading to the downregulation of type I IFN pathway.
Fig. 3: Rab37 downregulated type I IFN pathway through attenuation of STAT1 nuclear translocation.
Fig. 4: Rab37 sequestered STAT1 in the cytosol of macrophages in a GDP-dependent manner.
Fig. 5: Rab37 attenuated STAT1 and downregulated IFN-α expression in TAMs in vivo.
Fig. 6: The expression signature of CD163+/Rab37+/STAT1cytosol in TAMs was a biomarker for poor prognosis in lung cancer patients.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful for the support from the Human Biobank, Research Center of Clinical Medicine, National Cheng Kung University Hospital. We thank the technical services provided by the “Bioimaging Core Facility” of the National Core Facility for Biopharmaceuticals, Ministry of Science and Technology, Taiwan, and the support from the Core Research Laboratory, College of Medicine, National Cheng Kung University.

Funding

This work was supported by Taiwan Ministry and Science Technology grant MOST 109-2327-B-006-004 and Taiwan National Science and Technology Council grant NSTC 112-2311-B-006-004-MY3.

Author information

Author notes

  1. These authors contributed equally: Chen-Tai Hong, You-En Yang.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan, 701, Taiwan

    Chen-Tai Hong & Yi-Ching Wang

  2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan, 701, Taiwan

    You-En Yang, Chih-Peng Chang & Yi-Ching Wang

  3. Department of Life Science, National Taiwan University, No.1, Sec. 4, Roosevelt Road, Taipei, 106, Taiwan

    Hsueh-Fen Juan

  4. Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan, 701, Taiwan

    Chih-Peng Chang

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Contributions

Chen-Tai Hong: Writing – original draft, Writing – review & editing, Conceptualization, Methodology, Visualization, Formal analysis, Data curation. You-En Yang: Writing – original draft, Writing – revised draft, Writing – review & editing, Conceptualization, Methodology, Data curation, Investigation, Visualization. Hsueh-Fen Juan: Software, Data curation, Investigation. Chih-Peng Chang: Methodology, Validation, Investigation. Yi-Ching Wang: Supervision, Project administration, Conceptualization, Validation, Investigation, Funding acquisition, Data curation, Writing - original draft, Writing - review & editing.

Corresponding author

Correspondence to Yi-Ching Wang.

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Ethics approval and consent to participate

All experiments using mice were approved by the animal ethics committee of National Cheng Kung University and complied with all relevant ethical guidelines (#112062). All lung cancer samples were conducted in accordance with the requirements of Research Center of Clinical Medicine, National Cheng Kung University Hospital. The use of clinical samples was approved by the institutional review board of the hospital with the ethical number #A-ER-111-517. All patients provided informed consent for the use of the tumor tissues for research.

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Hong, CT., Yang, YE., Juan, HF. et al. GDP-bound Rab37 modulates M2-like tumor-associated macrophage polarization by attenuating STAT1 translocation to downregulate the type I IFN pathway. Br J Cancer 132, 622–634 (2025). https://doi.org/10.1038/s41416-025-02955-0

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