5′tRF‐GlyGCC Promotes Breast Cancer Progression via LDHA‐Mediated Glycolysis and Macrophage Polarization

Abstract Breast cancer (BC) progression is intricately linked to the dysregulation of transfer RNA‐derived fragments (tRFs). Through comprehensive analysis of The Cancer Genome Atlas (TCGA) data, it is demonstrated that 5′tRF‐GlyGCC is overexpressed in BC tissues and negatively associated with patients' survival. Mechanistically, 5′tRF‐GlyGCC binds to lactate dehydrogenase A (LDHA), enhancing its enzymatic activity and promoting glycolysis, which drives BC cell malignancy. This binding is mediated by the phosphorylation of LDHA at tyrosine 10, and facilitated by fibroblast growth factor receptor 1 (FGFR1), through the formation of a ternary complex that amplifies oncogenic signaling. Furthermore, 5′tRF‐GlyGCC/LDHA axis induces macrophage infiltration and polarization toward an M2 phenotype, mediated by the chemokine CCL7, thereby reshaping the tumor microenvironment. Additionally, it is uncovered that the biogenesis of 5′tRF‐GlyGCC is regulated by ALKBH3 and ANG, which also modulate LDHA activity. In vivo, targeting 5′tRF‐GlyGCC/LDHA signaling significantly suppresses tumor growth and enhances the efficacy of immunotherapy. Collectively, these findings elucidate the pivotal role of 5′tRF‐GlyGCC in BC progression, highlighting its potential as therapeutic target for BC treatment.