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 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.