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The USP1-WDR48 deubiquitinase complex functions as a molecular switch regulating tumor-associated macrophage activation and anti-tumor response

Cell Death & Differentiation (2025)Cite this article

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Abstract

M2-like tumor-associated macrophages (TAMs) are the main immunosuppressive cells infiltrating the tumor microenvironment (TME), the activation of which is essential for cancer progression and resistance promotion to immunotherapy. However, the regulatory mechanisms underlying TAM activation have not been fully elucidated. Utilizing a CRISPR-Cas9-based genetically engineered mouse model, we discovered that USP1fl/flLyz2cre/+ and WDR48fl/flLyz2cre/+ mice exhibited decreased tumor formation and lung metastasis. Mechanistically, the USP1-WDR48 deubiquitinase complex regulated M2-TAM activation and infiltration in the TME by modulating DDX3X ubiquitination. Specifically, this complex interacted with the N-terminal RecA-like domain 1 of DDX3X, leading to K48-linked deubiquitination and stabilization of DDX3X. Then, DDX3X promoted the translation of signaling molecules Jak1 and Rac1 via its RNA helicase activity, activating the Jak1-Stat3/6 and Rac1-Akt pathways to drive M2-TAM activation. Furthermore, combined inhibition of the USP1/WDR48 and CD47/SIRPĪ± signaling pathways showed synergistic antitumor effects in immunocompetent mice. Notably, USP1 protein expression in tumor stromal tissues independently predicts prognosis in breast cancer patients. These findings indicated the role of the USP1-WDR48 complex as a critical molecular switch controlling TAM activation, presenting novel and promising targets for breast cancer treatment.

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Fig. 1: Myeloid-specific deletion of USP1-WDR48 complex in mice inhibits E0771 tumor growth and lung metastasis.
Fig. 2: USP1-WDR48 complex enhances the tumor-promoting potential of TAMs in vitro.
Fig. 3: USP1-WDR48 complex facilitates M2-like TAMs activation.
Fig. 4: USP1-WDR48 complex targets DDX3X via interacting with the N-terminal RecA-like domain 1 of DDX3X.
Fig. 5: USP1-WDR48 complex decreases DDX3X ubiquitination and stabilizes DDX3X.
Fig. 6: USP1-WDR48 complex promotes M2-like TAM activation by increasing the RNA helicase activity of DDX3X.
Fig. 7: Targeting the USP1-WDR48 complex amplifies anti-CD47 immunotherapy in immunocompetent mice.
Fig. 8: The clinical significance of USP1 expression within the breast cancer microenvironment.

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Data availability

The LCā€“MS/MS data and uncropped images of immunoblots are included in the supplement. If necessary, more data can be provided from the corresponding author upon reasonable request.

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Funding

This research was supported by National Key Research and Development Program (No. 2020YFA0712400), Special Foundation for Taishan Scholars (No. ts20190971), Special Support Plan for National High Level Talents (Ten Thousand Talents Program W01020103), Foundation from Clinical Research Center of Shandong University (No.2020SDUCRCA015), Qilu Hospital Clinical New Technology Developing Foundation (No. 2019-3) to QY; National Natural Science Foundation of China (No. 82171734), the Shandong Provincial Natural Science Foundation (No. ZR2021MH048) to LW; National Natural Science Foundation of China (No. 82403732), China Postdoctoral Science Foundation (2023M742108), Shandong Postdoctoral Science Foundation (SDCX-ZG-202400073) to DH.

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Author notes

  1. These authors contributed equally: Dianwen Han, Lijuan Wang, Shan Jiang.

Authors and Affiliations

  1. Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China

    Dianwen Han,Ā Shan Jiang,Ā Tong Chen,Ā Ning Zhang,Ā Xiaolong Wang,Ā Yiran Liang,Ā Yaming Li,Ā Chen Li,Ā Xi Chen,Ā Dan LuoĀ &Ā Qifeng Yang

  2. Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

    Lijuan Wang,Ā Bing Chen,Ā Wenjing ZhaoĀ &Ā Qifeng Yang

  3. Department of Pathology, Qilu Hospital of Shandong University, Jinan, China

    Peng Su

  4. Research Institute of Breast Cancer, Shandong University, Jinan, China

    Qifeng Yang

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  1. Dianwen Han
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  2. Lijuan Wang
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Contributions

QY designed research studies. DH, LW, and SJ performed most of the experiments in this work. PS collected patient samples. TC and DL analyzed data. BC, WZ, NZ, XW, YRL, and YML provided valuable discussion. LW and DH wrote the manuscript.

Corresponding author

Correspondence to Qifeng Yang.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Breast cancer tissue specimens were collected from Qilu Hospital of Shandong University. This study was approved by the Research Ethics Committee of Qilu Hospital of Shandong University (KYLL-2016-255), with all participants providing informed consent and ensuring strict privacy protection. Animal experiments complied with Chinaā€™s Guidelines for Animal Health and Use and were approved by the Ethics Committee of Qilu Hospital of Shandong University (KYLL-2024(ZM)-436).

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Han, D., Wang, L., Jiang, S. et al. The USP1-WDR48 deubiquitinase complex functions as a molecular switch regulating tumor-associated macrophage activation and anti-tumor response. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01548-x

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