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

Sep 23, 2026

Therapeutic targeting of triple-negative breast cancer (TNBC) brain metastases remains a critical unmet clinical need. Roles of PIWI-interacting RNAs (piRNAs) in promoting brain metastasis are insufficiently understood, despite known dysregulation in cancer. This study identifies piR-1170 as a clinically relevant driver of TNBC brain metastasis through multi-model validation, linking its upregulation with poor survival and proposing a hnRNPK-stabilized mechanism and WTAP-mediated m6A reprogramming.

LanguageEnglish

CategoryResearch & Report

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Pages20

Reading Time50 min

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Abstract

Introduction

Luo etal. Molecular Cancer (2026) 25:52 Molecular Cancer [https://doi.org/10.1186/s12943-026-02568-y](https://doi.org/10.1186/s12943-026-02568-y) RESEARCH Open Access piR-1170 drives brain metastasis and immune evasion via WTAP-mediated m6A methylation reprogramming in triple-negative breast cancer Yongzhou Luo1†, WenwenTian2†, Xudong Zhu3,4†, Weidong Wei1†, Feng Ye1, Min-Yi Situ 1, Yuanliang Yan5, Xiaofang He6, Xuefang Huang1, Jun Tang1*, Yanan Kong1* and Hailin Tang1* Abstract 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 ofTNBC 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. †Yongzhou Luo, WenwenTian, Xudong Zhu and Weidong Wei contributed equally to this work. *Correspondence: Jun Tang [tangjun@sysucc.org.cn](tangjun@sysucc.org.cn)[ ](tangjun@sysucc.org.cn)Yanan Kong [kongyn@sysucc.org.cn](kongyn@sysucc.org.cn)[ ](kongyn@sysucc.org.cn)Hailin Tang [tanghl@sysucc.org.cn](tanghl@sysucc.org.cn) 1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, China 2Department of Plastic and Aesthetic Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China 3Department of General Surgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China 4Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA 5Department of Pharmacy, The Hunan Institute of Pharmacy Practice and Clinical Research, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 6Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by

FAQs

What is the main focus of the study in TNBC brain metastasis?

The study investigates how piR-1170 drives TNBC brain metastasis and immune evasion through WTAP-mediated m6A methylation reprogramming.

How does piR-1170 relate to patient outcomes in brain metastases?

Analysis of a TNBC cohort showed significant piR-1170 upregulation in brain metastases that correlates with poor patient survival.

What mechanism does the study propose for piR-1170-driven immune suppression?

Mechanistically, piR-1170 promotes WTAP expression to increase m6A methylation of DGAT2 and CD274 transcripts, activating lipid synthesis and PD-L1-driven immune suppression to support tumor adaptation and immune escape.

Sep 23, 2026

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