Extracellular vesicle-mediated tumor-nerve crosstalk: mechanisms and therapeutic opportunities

Accumulating evidence indicates that solid tumors actively recruit peripheral nerves into the tumor microenvironment (TME), where the infiltrating nerves profoundly influence tumor initiation, progression, metastasis, and therapeutic resistance. Beyond classical neural signaling, extracellular vesicles (EVs) have emerged as pivotal mediators of tumor-nerve communication. These nanoscale membrane-bound vesicles deliver oncogenic cargo (e.g., proteins and RNAs) that induces axonogenesis and reprograms neurons, thereby reshaping the neural niche to favor malignancy. EVs have also attracted growing attention for their important roles in coordinating the tripartite crosstalk among tumor cells, neurons, and immune cells, which fosters an immunosuppressive, pro-tumorigenic microenvironment. Furthermore, EVs orchestrate the glial, endothelial, and fibroblastic compartments, thereby embedding tumor-nerve communication within a broader multicellular network. In this review, we synthesize current insights into EV-mediated tumor-nerve crosstalk within the TME and evaluate the potential of EVs both as liquid-biopsy biomarkers for detecting perineural invasion and as therapeutic targets for disrupting pathological tumor innervation. Finally, we propose novel hypotheses and outline future directions for addressing the remaining challenges, with the aim of advancing tumor denervation therapies.