Melanoma exosomal hsa-miR-221-5p suppresses keratinocyte LL-37 to promote tumor progression

Melanoma progression is regulated by not only tumor-intrinsic factors but also dynamic crosstalk with the surrounding epidermis. Here, we observed spatial suppression of cathelicidin LL-37 in tumor-adjacent epidermis compared with that in distal regions in clinical specimens. We further found that melanoma-derived exosomes suppressed keratinocyte LL-37 expression, which was driven in part by exosomal hsa-miR-221-5p through impaired sustained EGFR signaling. Functionally, keratinocyte-derived LL-37 curtailed melanoma cell migration, invasion, and epithelial-mesenchymal transition; restrained tumor growth in vivo; and was associated with a tumor immune microenvironment enriched in M1 macrophages and N1 neutrophils. Together, these findings reveal an epidermal-tumor interaction in which melanoma exosomal microRNAs (miRNAs) may weaken keratinocyte host defenses, whereas keratinocyte-derived LL-37 appears to counteract melanoma progression and immunosuppression. These observations expand the current understanding of tumor-epidermal communication and raise the possibility that the preservation or augmentation of LL-37 signaling could represent a therapeutic strategy against melanoma.