September 3, 2026, 11:03 am | Read time: 5 minutes
Cancer cells do not grow in isolation. They are in constant communication with the healthy cells around them–and can alter their behavior to their own advantage. Researchers have now closely examined such a mechanism in malignant melanoma, or black skin cancer. At the center of this is a specific molecule that is actually part of the skin’s natural defense against pathogens.
How Melanoma Cells Influence Their Environment
The study shows that melanoma cells can specifically reduce the production of the molecule LL-37 in neighboring skin cells. To do this, the cancer cells send out tiny vesicles (exosomes) that transport certain RNA molecules to the skin cells, where they suppress the formation of LL-37.1
This could give the tumor an advantage. However, the defense molecule LL-37 has a double life: In very small amounts, it can paradoxically even stimulate tumor growth. Only in medium to high concentrations does it act as an effective cancer brake, blocking the growth and spread of melanoma cells in the lab.
How the Study Was Conducted
LL-37 is produced, among other things, by keratinocytes, the most common cells in the epidermis. The molecule is primarily known as part of the body’s defense against bacteria and other pathogens. Its role in cancer, however, is not clear and seems to depend on the type of tumor.
The researchers wanted to find out how LL-37 works in melanoma and whether tumor cells can influence its production in surrounding skin cells.
To do this, they combined various methods. They examined tissue samples from four people with melanoma, conducted experiments with human melanoma and skin cells in the lab, and analyzed the exosomes released by the cancer cells. Additionally, they studied tumor growth in mice that lacked the mouse equivalent of LL-37 in certain skin cells. In further experiments, they reintroduced this molecule.
How Melanoma Weakens the Skin’s Protective Function
In skin samples, the researchers found less LL-37 directly next to the tumor than in more distant areas. Laboratory experiments showed how melanoma might achieve this: The cancer cells release tiny vesicles that transport certain molecules to neighboring skin cells. One of these, the so-called micro-RNA “miR-221-5p,” can cause these skin cells to produce less LL-37.
This could help the tumor grow. As the researchers observed in the lab, the molecule effectively slows the proliferation of melanoma cells when present in the right, sufficiently high concentration. It makes it harder for them to spread and invade surrounding tissue. This effect was also seen in mice: When they lacked the corresponding molecule, larger tumors grew. When it was administered to the animals, tumor growth slowed.
LL-37 also influenced the immune response around the tumor. With the molecule, the researchers found more immune cells that can help fight tumors. In its absence, the environment was more conducive to a weakened immune response against cancer.
The results thus suggest a kind of interplay between melanoma and healthy skin: LL-37 can apparently slow the tumor in several ways. The melanoma, in turn, seems to ensure that the skin produces less of it.
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Strengths and Weaknesses of the Study
The study has the advantage that the researchers combined various methods. They examined tissue from patients, conducted experiments with cells in the lab, and verified their results in animal experiments. This allowed them to investigate possible biological connections from different perspectives.
However, there are limitations. The tissue samples came from only four patients, all of whom belonged to the Han Chinese population group. It is therefore unclear how well the results can be generalized to other population groups and genders. Additionally, the exosome experiments were conducted with cultured melanoma cell lines. Whether exosomes in patients’ blood have the same effect still needs to be investigated.
The animal experiments with imiquimod are also only of limited significance, as the cream activates the immune system in several ways, and the cancer-inhibiting effect cannot be clearly attributed to mCRAMP. Finally, while it is known that miR-221-5p influences skin defense, its direct molecular targets in the EGFR signaling pathway are still unclear.
The authors reported no conflicts of interest. The study was funded in part by Japanese research programs and scientific foundations.
What Other Studies Show
The role of LL-37 in cancer is controversial–and particularly so in melanoma. A study by Japanese dermatologists in 2023 reached an opposite conclusion: The deeper the melanoma had grown, the more LL-37 was found in the tumor tissue. When the molecule was administered to melanoma cells or mice, the production of signaling substances that promote new blood vessel formation and thus tumor growth increased.2
The contradiction is less surprising than it seems. LL-37 acts differently in various types of cancer–promoting in ovarian, lung, and breast cancer, and inhibiting in colon and stomach cancer. There is also a methodological difference: The new study examines endogenous LL-37 from skin cells around the tumor. In the counter-studies, the molecule was usually added externally and in comparatively high concentrations. Whether LL-37 inhibits or drives depends on where it comes from and how much is present.
The idea of using micro-RNAs as future markers in the blood is also not yet fully developed. A review from 2026 summarized ten studies with around 1,150 melanoma patients.3 Combinations of several micro-RNAs correctly identified the disease in about nine out of ten cases. However, the authors caution that almost all studies used a design that systematically overestimates the hit rate, and the results varied greatly. Confirmation for practical use is still lacking.