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<p>Therapeutic target for triple-negative breast cancer (TNBC) brain metastases remains a critical unmet clinical challenge. The roles of PIWI-interacting RNAs (piRNAs) in driving brain metastasis are poorly understood, despite their known dysregulation and oncogenic functions in cancer. Here, we identified piR-1170 as a clinically relevant driver of TNBC brain metastasis through multi-model validation. Analysis of the TNBC cohort from Sun Yat-sen University Cancer Center revealed significant piR-1170 upregulation in brain metastases correlating with poor patient survival. First, upstream analysis confirmed that hnRNPK binds to piR-1170 to maintain the piRNA's stability, thereby sustaining piR-1170 upregulation in TNBC. Then, Functional studies with metastasis models demonstrated the brain-specific metastatic activity of piR-1170, enhancing tumor cell adhesion to brain endothelia, vascular extravasation, and parenchymal invasion. Mechanistically, piR-1170 promotes WTAP expression to enhance m6A methylation of <i>DGAT2</i> and <i>CD274</i> transcripts, activating de novo lipid synthesis and PD-L1-driven immune suppression to promote tumor adaptation to lipid-scarce metastases and avoid immune surveillance. Our study defined the piR-1170-driven axis that operates through coordinated metabolic reprogramming and immunosuppression, thus revealing its potential as a therapeutic candidate for TNBC brain metastasis.</p>

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piR-1170 drives brain metastasis and immune evasion via WTAP-mediated m6A methylation reprogramming in triple-negative breast cancer

  • 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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  • Yongzhou Luo,
  • Wenwen Tian,
  • Xudong Zhu,
  • Weidong Wei,
  • Feng Ye,
  • Min-Yi Situ,
  • Yuanliang Yan,
  • Xiaofang He,
  • Xuefang Huang,
  • Jun Tang,
  • Yanan Kong,
  • Hailin Tang

摘要

Therapeutic target for triple-negative breast cancer (TNBC) brain metastases remains a critical unmet clinical challenge. The roles of PIWI-interacting RNAs (piRNAs) in driving brain metastasis are poorly understood, despite their known dysregulation and oncogenic functions in cancer. Here, we identified piR-1170 as a clinically relevant driver of TNBC brain metastasis through multi-model validation. Analysis of the TNBC cohort from Sun Yat-sen University Cancer Center revealed significant piR-1170 upregulation in brain metastases correlating with poor patient survival. First, upstream analysis confirmed that hnRNPK binds to piR-1170 to maintain the piRNA's stability, thereby sustaining piR-1170 upregulation in TNBC. Then, Functional studies with metastasis models demonstrated the brain-specific metastatic activity of piR-1170, enhancing tumor cell adhesion to brain endothelia, vascular extravasation, and parenchymal invasion. Mechanistically, piR-1170 promotes WTAP expression to enhance m6A methylation of DGAT2 and CD274 transcripts, activating de novo lipid synthesis and PD-L1-driven immune suppression to promote tumor adaptation to lipid-scarce metastases and avoid immune surveillance. Our study defined the piR-1170-driven axis that operates through coordinated metabolic reprogramming and immunosuppression, thus revealing its potential as a therapeutic candidate for TNBC brain metastasis.