A tumor-derived mitochondrial tsRNA drives vascular invasion of lung adenocarcinoma by promoting ribosomal assembly in endothelial cells

Vascular invasion is associated with metastasis and poor prognosis in patients with lung adenocarcinoma (LUAD). Recent studies have highlighted the role of intercellular mitochondrial transfer, mediated by both contact-dependent and contact-independent mechanisms, in tumor progression. Here, we reveal an abnormal accumulation of mitochondria in vascular endothelial cells invaded by tumor cells. Further in vivo and in vitro experiments demonstrated that tumor cells can transfer mitochondria with highly expressed mitochondrial tRNA-derived small RNAs (tsRNAs), mt-5'tiRNA-34-GlnTTG, to endothelial cells. Mechanistic investigations indicated that mt-5'tiRNA-34-GlnTTG binds to FUBP3 and facilitates its translocation, ultimately enhancing ribosomal assembly efficiency and translation rates in endothelial cells. This molecular cascade leads to increased endothelial cell proliferation and migration, thereby promoting LUAD metastasis. Moreover, we demonstrated the potential clinical translational value of lipid nanoparticles(LNPs) encapsulating mt-5'tiRNA-34-GlnTTG inhibitors in animal experiments. Utilizing LNPs encapsulating mt-5'tiRNA-34-GlnTTG inhibitors effectively suppressed lung cancer metastasis in in vivo models. These findings reveal a novel mechanism of LUAD progression mediated by mitochondrial tsRNA transfer and highlight a promising therapeutic strategy for limiting metastatic spread.