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Translational Therapeutics

RNA methylation of CD47 mediates tumor immunosuppression in EGFR-TKI resistant NSCLC

British Journal of Cancer volume 132, pages 569–579 (2025)Cite this article

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Abstract

Background

Although immune checkpoint inhibitors (ICIs) have been successfully utilized in patients with non-small cell lung cancer (NSCLC), EGFR-mutated patients didn’t benefit from ICIs. The underlying mechanisms for the poor efficacy of this subgroup remain unclear.

Methods

CD8+T cells cytotoxicity, DCs phagocytosis and immunofluorescence assay were applied to examine the immunosuppressive microenvironment of NSCLC. m6A RNA immunoprecipitation, luciferase assay and immunohistochemistry were used to explore the relationship between CD47 and ALKBH5 in EGFR-TKI resistant NSCLC. Autochthonous EGFR-driven lung tumor mouse model and PDXs were performed to explore the therapeutic potential of CD47 antibody and EGFR-TKI combination.

Results

We found that EGFR-TKI resistance promoted a more immunosuppressive tumor microenvironment and inhibited anti-tumor functions of CD8+ T cells. Mechanistically, the m6A eraser ALKBH5 was inhibited in EGFR-TKI resistant NSCLC, which subsequently upregulates CD47 by catalyzing m6A demethylation and causes immunosuppression. Combined treatment with EGFR-TKI and inhibitors of CD47 enhances antitumor immunity and EGFR-TKI efficacy in vivo.

Conclusions

Collectively, our findings reveal the possible underlying mechanism for poor immune response of ICIs in EGFR-TKI resistant NSCLC and provide preclinical evidence that targeted therapy combined with innate immune checkpoint blockade may provide synergistic effects in NSCLC treatment.

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Fig. 1: EGFR-TKI resistant NSCLC are immunosuppressive.
Fig. 2: CD47 mediates the immunosuppressive effect of EGFR-TKI resistant NSCLC.
Fig. 3: ALKBH5 regulates CD47 expression by catalyzing m6A demethylation.
Fig. 4: ALKBH5-mediated CD47 upregulation is associated with poor outcome.
Fig. 5: Block of CD47 improve immune response and synergize with EGFR-TKI.
Fig. 6: Schematics of signaling network of ALKBH5 and CD47 in controlling immunosuppression of NSCLC microenvironment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82073121) and Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515010041).

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Author notes

  1. These authors contributed equally: Wei Zhang, Jiawen Wang, Jialu Liang.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Wei Zhang, Jiawen Wang, Jialu Liang, Zhanghai He, Kefeng Wang & Huayue Lin

  2. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Wei Zhang, Jiawen Wang & Huayue Lin

  3. Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Jialu Liang & Kefeng Wang

  4. Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Zhanghai He

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  6. Huayue Lin
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Contributions

KW and HL conceived and designed the experiments. WZ, JW, JL and ZH performed the experiments. WZ and JW analyzed the data. HL and KW wrote the paper. All authors approved the final manuscript.

Corresponding authors

Correspondence to Kefeng Wang or Huayue Lin.

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Competing interests

The authors declare no competing interests.

Consent for publication

All authors have reviewed the final version of the manuscript and are in agreement its content and submission.

Ethics approval and consent to participate

The study was conducted following the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committees of Sun Yat-Sen Memorial Hospital (SYSEC-KY-KS-2019-189). The animal procedures were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University (AP20220148). All methods were carried out in accordance with relevant guidelines and regulations.

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Zhang, W., Wang, J., Liang, J. et al. RNA methylation of CD47 mediates tumor immunosuppression in EGFR-TKI resistant NSCLC. Br J Cancer 132, 569–579 (2025). https://doi.org/10.1038/s41416-025-02945-2

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