Exosomal Oleic Acid Promotes Lymphangiogenesis and Nodal Metastasis in Cervical Cancer via the AKT/mTOR Pathway

ABSTRACT

Cervical cancer (CC) exhibits a pronounced tropism for regional lymphatic dissemination, a process driven by tumor‐associated lymphangiogenesis. While metabolites within the metastatic niche are increasingly recognized as determinants of organotropic metastasis, the role of exosome‐mediated metabolite transfer in tumor‐lymphatic endothelial cell (LEC) crosstalk remains largely unexplored. Here, we demonstrate that oleic acid (OA) is significantly enriched in both CC lymph node metastases and the peritumoral lymphatic microenvironment. Exosomes derived from highly metastatic CC cells actively package OA in a manner dependent on stearoyl‐CoA desaturase (SCD), the rate‐limiting enzyme of de novo fatty acid synthesis. Upon internalization by LECs, exosomal OA triggers the AKT/mTOR signaling axis, eliciting robust LEC proliferation and endothelial‐to‐mesenchymal transition (EndMT), thereby fostering lymphangiogenesis and nodal colonization. Knockdown of SCD abolishes these pro‐lymphangiogenic effects, a deficit fully reversed by the reconstitution of OA‐loaded exosomes. In vivo, exosomes from SCD‐silenced cells exhibit a severely compromised capacity to drive primary tumor growth, intratumoral lymphangiogenesis, and lymph node metastasis (LNM). Notably, free OA administration exerts substantially weaker effects than its exosomal counterpart, underscoring the superior efficiency of exosome‐mediated metabolite trafficking. Clinically, FASN and SCD expression are significantly upregulated in lymph node‐positive specimens and positively correlate with lymphatic vessel density and p‐AKT levels. Furthermore, circulating exosomal OA levels are significantly elevated in patients with nodal involvement, suggesting its potential as a non‐invasive diagnostic biomarker. Collectively, our findings establish a paradigm wherein tumor‐derived exosomes function as specialized vehicles for intercellular OA transfer, activating the AKT/mTOR pathway to license lymphangiogenic reprogramming. This work identifies exosomal metabolite shuttling as a central node in tumor‐lymphatic communication and proposes targeting OA synthesis or exosomal delivery as a promising therapeutic strategy against CC metastasis.