36 Cancers actively remodel the cells and tissues around them to create a microenvironment that supports their growth, survival, and spread. Melanoma, a cancer of the pigment-producing melanocytes in the skin, is one of the most aggressive forms of skin cancer and can rapidly metastasise if not detected and treated early. Researchers from the Atopy (Allergy) Research Center at Juntendo University Graduate School of Medicine in Japan, led by Professor François Niyonsaba, together with co-authors Quan Sun and Ge Peng, investigated the relationship between melanoma cells and keratinocytes, the most abundant cells in the skin that surround melanoma cells. Their findings were made available online on 12th August 2026 and published in Volume 45, Issue 8 of Cell Reports on 25th August 2026. “Melanoma originates from melanocytes located within the epidermal environment, where tumour cells are surrounded by and continuously communicate with keratinocytes. However, most studies of the melanoma microenvironment have focused on immune cells, fibroblasts, and vascular cells, while the contribution of neighbouring epidermal keratinocytes has received comparatively less attention,” says Dr Sun, the first author of the paper, explaining the motivation behind the study. The team analysed human melanoma specimens and found that LL-37, a protective antimicrobial peptide produced by keratinocytes, was selectively reduced in the keratinocytes immediately surrounding melanoma cells, while remaining at normal levels farther from the tumour. “This spatial pattern suggested that melanoma cells may actively alter the biological function of neighbouring keratinocytes,” explains Professor Niyonsaba. The researchers confirmed this by showing that co-culturing melanoma cells with keratinocytes reduced LL-37 production. Exosomes are small extracellular vesicles that act as important carriers of signals, including miRNAs, between cells. The researchers found that exosomes derived from melanoma cells reduced LL-37 levels in cultures of human keratinocytes. Blocking exosome production with manumycin A further confirmed that exosomal signalling was responsible for the reduction. “Detailed miRNA analysis demonstrated that melanoma cells release extracellular vesicles, particularly exosomes carrying the miRNA ‘hsa-miR-221-5p’, which are taken up by keratinocytes and suppress LL-37 expression,” says Dr Peng. “Through this mechanism, melanoma cells weaken a local epithelial defence pathway called ‘EGFR’ that would otherwise restrain tumour progression,” he explains. Using mouse and cell models of melanoma, the team also investigated LL-37’s antitumour role. LL-37 counteracted melanoma progression by suppressing tumour cell proliferation and spread, while also recruiting beneficial immune cells such as M1 macrophages and N1 neutrophils that support antitumour defence. The researchers also found that LL-37 inhibited signalling pathways including P2X7/PI3K/AKT and autophagy, suggesting that its protective effects extend beyond directly restricting tumour cell growth. “This tumour–epidermis ‘arms race’ provides a new understanding of how melanoma remodels its surrounding tissue and suggests that strengthening epithelial defence mechanisms may offer a complementary therapeutic strategy for melanoma,” Professor Niyonsaba says. The findings point to several molecular targets that could inform future melanoma treatments. LL-37-based therapies could potentially restrict melanoma progression directly, while the exosomal pathway could be targeted at several stages. These include blocking the release or uptake of tumour-derived exosomes, neutralising exosomal hsa-miR-221-5p, or preventing its downstream effects in keratinocytes. LL-37 expression and exosomal hsa-miR-221-5p could also have potential as biomarkers. The study highlights an anticancer defence mechanism that is naturally present in healthy skin and suggests how it might be therapeutically exploited. Strengthening the skin’s own epithelial barriers could provide a complementary approach alongside treatments directed at the tumour or immune system.