Molecular Mechanisms and Therapeutic Applications of Extracellular Vesicles in Remodeling of the Skin Cancer Niche

ABSTRACT

Skin cancer, encompassing melanoma and nonmelanoma types, is an escalating global health issue owing to its increasing prevalence, invasiveness, and spreading capability. Extracellular vesicles (EVs) have become pivotal agents of intercellular communication in the tumor microenvironment (TME). These nano‐ to microscale, membrane‐bound vesicles are released by tumor, stromal, and immune cells and transport bioactive substances such as proteins, lipids, and nucleic acids that influence recipient‐cell behavior. EVs are produced via endosomal sorting or plasma membrane budding, yielding exosomes and microvesicles with unique molecular signatures. In skin cancer, EV cargo mirrors, the genetic and metabolic state of the originating cell, containing abundant integrins, matrix metalloproteinases, growth factors, and regulatory microRNAs that modulate proliferation, survival, and stress responses. Tumor‐derived EVs facilitate immune evasion by delivering immune checkpoint molecules such as PD‐L1, thereby inhibiting cytotoxic T cell activity and promoting regulatory T cell expansion. They promote angiogenesis and transform fibroblasts into cancer‐associated fibroblasts, thereby aiding extracellular matrix remodeling and invasion. Moreover, EVs facilitate metastasis by creating pre‐metastatic habitats and enhancing vascular permeability. EVs are promising targets for diagnostic and therapeutic approaches at disrupt tumor‐supportive communication networks.