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m6A modification-dependent upregulation of WNT2 facilitates M2-like macrophage polarization and perpetuates malignant progression of nasopharyngeal carcinoma

Oncogene (2025)Cite this article

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Abstract

The development and progression of nasopharyngeal carcinoma (NPC) involves intricate interactions between tumor cells and other surrounding cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play pivotal roles in the progression of NPC, but their interactions remain largely unexplored. In this study, we revealed that NPC promoted M2-like polarization of TAMs through enhanced synthesis and secretion of WNT2. These M2-type macrophages, in turn, significantly boosted the proliferation and metastasis of NPC. This vicious cycle perpetuated the malignant progression of NPC. Mechanistically, elevated m6A modification of WNT2 in NPC stabilized its mRNA and facilitated its protein expression, which is coordinately regulated by the m6A “eraser” ALKBH5 and the “reader” YTHDF1. NPC promoted M2-like polarization of macrophages by activating the FZD2/β-catenin signaling axis through paracrine WNT2. Furthermore, elevated WNT2 can also trigger the WNT/β-catenin signaling pathway in NPC cells through autocrine signaling, synergically contributing to NPC development. The research reveals that WNT2 is upregulated in an m6A modification-dependent manner and promotes M2-like macrophages polarization of TAMs and malignant progression of NPC. This discovery provides novel potential molecular markers and therapeutic targets for the diagnosis and treatment of NPC.

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Fig. 1: WNT2 is highly expressed in NPC and closely associated with poor prognosis of NPC patients.
Fig. 2: WNT2 promotes M2-like macrophage polarization through activating the FZD2/β-catenin signaling pathway in macrophages.
Fig. 3: M2-like macrophages promote the proliferation and metastasis of NPC.
Fig. 4: Autocrine WNT2 promotes proliferation, migration, and invasion of NPC cells.
Fig. 5: m6A modification augments the expression and secretion of WNT2 and is negatively regulated by ALKBH5.
Fig. 6: YTHDF1 and ALKBH5 coordinately modulate WNT2 mRNA stability in an m6A-dependent manner.
Fig. 7: The expression of WNT2 in NPC tissue is positively correlated with M2-like macrophage polarization and negatively correlated with ALKBH5 expression.

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Data availability

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

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Acknowledgements

The authors acknowledge the BioRender (www.biorender.com), as Fig. S2C, 3A and 7E in this article was created with BioRender platform. This study was funded by the National Natural Science Foundation of China (U21A20382), the Natural Science Foundation of Hunan Province (2024JJ3035), and the Natural Science Foundation of Changsha (kh2301025), and the Fundamental Research Funds for the Central Universities of Central South University (2024ZZTS0529).

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Authors and Affiliations

  1. NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China

    Qiling Tang, Pan Chen, Lei Shi, Zhaoyang Zeng & Wei Xiong

  2. Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China

    Qiling Tang, Lvyuan Li, Junshang Ge, Dan Wang, Hongke Qu, Jie Wu, Qian Wang, Zhouying Peng, Yongzhen Mo, Yumin Wang, Chunmei Fan, Qijia Yan, Pan Chen, He Huang, Lei Shi, Zhaoyang Zeng & Wei Xiong

  3. FuRong Laboratory, Changsha, Hunan, China

    Qiling Tang, Lvyuan Li, He Huang, Zhaoyang Zeng & Wei Xiong

  4. Departments of Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China

    Jie Wu, Yumin Wang & Wenjia Guo

  5. Xinjiang Key Laboratory of Translational Biomedical Engineering, Urumqi, China

    Jie Wu & Wenjia Guo

  6. Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Zhouying Peng, Yongzhen Mo, Yumin Wang & Qijia Yan

  7. Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Lei Shi

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  1. Qiling Tang
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Contributions

QLT designed the project and completed most experiments., LYL, JSG, DW, HKQ performed some of the experiments. JW, QW, ZYP, YZM collected tissue samples. QLT analyzed the data and wrote the manuscript. YMW, CMF, QJY, PC, HH, WJG, LS, ZYZ, and WX revised the manuscript. LS, PC, and WX are responsible for research supervision and funding acquisition. All authors read and approved the final manuscript.

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Correspondence to Lei Shi, Zhaoyang Zeng or Wei Xiong.

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All animal studies were approved by the Laboratory Animal Ethics Committee of Central South University (Approval No: CSU-2022-0569). All animal experiments strictly adhered to the ethical guidelines and regulations of the committee.

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Tang, Q., Li, L., Ge, J. et al. m6A modification-dependent upregulation of WNT2 facilitates M2-like macrophage polarization and perpetuates malignant progression of nasopharyngeal carcinoma. Oncogene (2025). https://doi.org/10.1038/s41388-025-03452-7

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