Study reveals how melanoma weakens skin cell immune defenses

Cancers actively remodel their surrounding cells and tissues to create a microenvironment that favors their growth, survival, and spread. Melanoma, the cancer of the pigment-producing melanocytes of the skin, is one of the most aggressive skin cancers and can rapidly metastasize if not detected and treated early. Researchers from the Atopy (Allergy) Research Center of the Juntendo University Graduate School of Medicine, Japan, led by Prof. François Niyonsaba, along with co-authors Quan Sun and Ge Peng, explored the relationship between melanoma cells and keratinocytes, the majority cells of the skin that surround melanoma cells. Their findings were made available online on August 12, 2026, and published in Volume 45, Issue 8 of Cell Reports on August 25, 2026.

"Melanoma originates from melanocytes located within the epidermal environment, where tumor 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 neighboring epidermal keratinocytes has received comparatively less attention," says Dr. Quan Sun, the first author of the paper, about the motivation behind the study.

They analyzed human melanoma specimens. LL-37, a protective antimicrobial peptide produced by the keratinocytes, was found to be selectively reduced in the keratinocytes immediately surrounding the melanoma cells, whereas it was found at normal levels in areas farther from the tumor. "This spatial pattern suggested that melanoma cells may actively alter the biological function of neighboring keratinocytes," explains Prof. Niyonsaba. When melanoma cells were cultured with keratinocytes, their LL-37 production was reduced, confirming their suspicion.

Exosomes are small vesicles that are the major carriers of signals like miRNAs from one cell to its neighbors. The melanoma-derived exosomes were found to reduce LL-37 in cultures of human keratinocytes. Furthermore, blocking exosome production using a drug called manumycin A confirmed that exosomal signals were responsible for the reduced LL-37 production. "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 defense pathway called 'EGFR' that would otherwise restrain tumor progression," he explains.

Further, they also explored the antitumor role of "LL-37" using mouse and cell models of melanoma. LL-37 was found to counteract melanoma progression by suppressing cell proliferation and spread. It also recruited other beneficial immune cells like M1 macrophages and N1 neutrophils that aid in antitumor defense. Furthermore, signaling pathways like P2X₇/PI3K/AKT signaling and autophagy were also inhibited, indicating that its protective effects extend beyond direct tumor-cell inhibition.

In summary, melanoma-derived exosomal signals suppress keratinocyte LL-37 production, whereas keratinocyte-derived LL-37 counteracts melanoma progression. "This tumor–epidermis 'arms race' provides a new understanding of how melanoma remodels its surrounding tissue and suggests that strengthening epithelial defense mechanisms may offer a complementary therapeutic strategy for melanoma," Prof. Niyonsaba is optimistic.

Each of these molecular targets could be explored for the development of melanoma treatment modalities. LL-37-based therapeutics could directly restrict melanoma progression. On the flip side, melanoma-derived exosomal pathway can also be blocked at various stages, such as the release or uptake of tumor-derived exosomes, neutralizing the exosomal hsa-miR-221-5p, or preventing its downstream effects in keratinocytes. Furthermore, LL-37 expression or exosomal hsa-miR-221-5p might find application as potential biomarkers. Overall, this study sheds light on active anticancer defense mechanisms inherent to normal skin and how they can be therapeutically exploited.