Lymphatic extracellular vesicles and non-coding rnas in the melanoma sentinel lymph node pre-metastatic niche: Emerging lessons from aggressive skin cancers.

Sentinel lymph node (SLN) involvement remains one of the strongest prognostic markers in cutaneous melanoma; however, the SLN is not merely a staging specimen. It is the first organized immune-stromal site exposed to lymph-borne melanoma-derived extracellular vesicles (EVs), soluble mediators, proteins, lipids, and non-coding RNAs (ncRNAs) before and during metastatic seeding. Current evidence supports a model in which melanoma-derived EVs traffic through lymphatic vessels, enter draining nodes, interact with lymphatic endothelial cells, medullary macrophages, dendritic cells, and T cells, and remodel lymphovascular, stromal, and immune compartments. Key vesicle-associated mechanisms include NGFR/p75NTR-positive small extracellular vesicles (sEVs) that drive lymphangiogenesis and nodal metastasis, PD-L1-positive vesicles that suppress T-cell activation, CD36-linked pathways that reshape myeloid lipid metabolism, and uPAR-associated vesicles that promote endothelial and matrix remodeling. EV-associated miRNAs, lncRNAs, and circRNAs may further regulate fibroblast activation, macrophage behavior, MAPK/ERK signaling, PTEN-related stromal restraint, glycolysis, autophagy, and tumor-suppressive pathways. This review integrates clinical SLN biology, lymphatic vesicle trafficking, cargo-specific protein and ncRNA pathways, immune tolerance, stromal remodeling, multi-omic profiling, and therapeutic interception. Comparative evidence from cutaneous squamous cell carcinoma and Merkel cell carcinoma broadens the field, but direct evidence linking lymphatic EVs to SLN remodeling remains strongest in melanoma.