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Background <p>Neutrophils, serving as crucial innate immune cells, exert anti-tumor effects through cytotoxic mediators, antibody-dependent responses, and coordination of immune networks. They also release exosomes that carry bioactive molecules such as microRNAs (miRNAs). Our previous work identified neutrophil-derived exosomes (N-Exo) as contributors to their anti-tumor activity, but the underlying mechanisms remain unclear.</p> Methods <p>Functional experiments integrating high-throughput sequencing and validation assays were performed to screen and identify key anti-tumor miRNAs in N-Exo. An in vivo subcutaneous xenograft mouse tumor model assessed the therapeutic effects of N-Exo-delivered miR-101-3p on tumor growth. Bioinformatics analysis combined with experimental validation, including dual-luciferase reporter assays, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP), elucidated the mechanism by which the key miRNA suppresses tumorigenesis through targeting specific genes and signaling pathways. Recombinant interleukin-36 gamma (rmIL-36γ) was used to stimulate neutrophils, and functional assays were performed to evaluate its effect.</p> Results <p>Hsa-miR-101-3p was enriched in N-Exo. N-Exo-delivered miR-101-3p directly targets MCL1 to suppress its expression and indirectly inhibits MCL1 transcription via regulation of the EZH2/c-Myc axis, collectively promoting apoptosis in gastric cancer (GC) cells. Furthermore, rmIL-36γ priming upregulated miR-101-3p expression in neutrophils and enhanced their anti-tumor effects.</p> Conclusion <p>We demonstrate that N-Exo exerts tumor-suppressive effects by delivering miR-101-3p, which dually targets and suppresses MCL1 expression. Moreover, rmIL-36γ treatment enhances both miR-101-3p abundance and anti-tumor efficacy in neutrophils. These findings highlight the N-Exo/miR-101-3p/MCL1 axis as a therapeutic target and support cytokine priming as a strategy to enhance neutrophil-based cancer therapy.</p>

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Neutrophil-derived exosomes inhibit gastric cancer progression via miR-101-3p-mediated suppression of MCL1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Jiayi Wang,
  • Jiahui Zhang,
  • Yu Qian,
  • Yanzhen Wang,
  • Shuwen Wang,
  • Baiyuan Fan,
  • Jiayuan Shi,
  • Jing Wang,
  • Shuting Meng,
  • Xiaotong Dong,
  • Min Fu,
  • Xiaoxin Zhang,
  • Runbi Ji,
  • Xinjian Fang,
  • Xu Zhang

摘要

Background

Neutrophils, serving as crucial innate immune cells, exert anti-tumor effects through cytotoxic mediators, antibody-dependent responses, and coordination of immune networks. They also release exosomes that carry bioactive molecules such as microRNAs (miRNAs). Our previous work identified neutrophil-derived exosomes (N-Exo) as contributors to their anti-tumor activity, but the underlying mechanisms remain unclear.

Methods

Functional experiments integrating high-throughput sequencing and validation assays were performed to screen and identify key anti-tumor miRNAs in N-Exo. An in vivo subcutaneous xenograft mouse tumor model assessed the therapeutic effects of N-Exo-delivered miR-101-3p on tumor growth. Bioinformatics analysis combined with experimental validation, including dual-luciferase reporter assays, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP), elucidated the mechanism by which the key miRNA suppresses tumorigenesis through targeting specific genes and signaling pathways. Recombinant interleukin-36 gamma (rmIL-36γ) was used to stimulate neutrophils, and functional assays were performed to evaluate its effect.

Results

Hsa-miR-101-3p was enriched in N-Exo. N-Exo-delivered miR-101-3p directly targets MCL1 to suppress its expression and indirectly inhibits MCL1 transcription via regulation of the EZH2/c-Myc axis, collectively promoting apoptosis in gastric cancer (GC) cells. Furthermore, rmIL-36γ priming upregulated miR-101-3p expression in neutrophils and enhanced their anti-tumor effects.

Conclusion

We demonstrate that N-Exo exerts tumor-suppressive effects by delivering miR-101-3p, which dually targets and suppresses MCL1 expression. Moreover, rmIL-36γ treatment enhances both miR-101-3p abundance and anti-tumor efficacy in neutrophils. These findings highlight the N-Exo/miR-101-3p/MCL1 axis as a therapeutic target and support cytokine priming as a strategy to enhance neutrophil-based cancer therapy.