Article

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

Mustafa T ArdahFaculty of Allied Medical Sciences, Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan. Electronic address: [email protected]Umida TashkenbaevaDepartment of dermatovenerology and cosmetology N1, Tashkent State Medical University, Tashkent, Uzbekistan. Electronic address: [email protected]Abdulqader Faris AbdulqaderCollege of Pharmacy, Alnoor University, Nineveh, Iraq. Electronic address: [email protected]Amir Abdul KadhimDepartment of Medical Laboratory Technologies, College of Medical Technology, The Islamic University, Najaf, Iraq. Electronic address: [email protected]K.V. JamunaDepartment of Forensic Science, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India. Electronic address: [email protected]Divya SinghalCentre for Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India; Sharda School of Bio-Science & Technology, Sharda University, Greater Noida, India. Electronic address: [email protected]Neeraj BainsalUniversity Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India. Electronic address: [email protected]Anajan MadashevaDepartment of Hematology, Samarkand State Medical University, Samarkand, Uzbekistan. Electronic address: [email protected]

2026en

ABI

Abstract

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.

Identifiers

DOI: 10.1016/j.ctarc.2026.101298

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