Melatonin May Offer a Surprising Shield Against Skin Cancer, Review Suggests

Melatonin, the hormone best known for lulling us to sleep, may have a second career waiting in dermatology. A new hypothesis-oriented review published in the Archives of Dermatological Research argues that this indolamine, produced chiefly by the pineal gland during darkness, could serve as a complementary strategy for preventing and managing skin cancer, the most common malignancy worldwide. The review, led by Luiza A. Altenfelder of the Federal University of São Paulo together with sleep researchers Ellen M. S. Xerfan, Sergio Tufik, and Monica L. Andersen, synthesizes 61 studies spanning cell cultures, animal models, and limited human data to build a case that melatonin’s antioxidant, anti-inflammatory, and immunomodulatory properties directly intersect with the molecular pathways driving skin carcinogenesis.

The stakes are considerable. Non-melanoma skin cancer, comprising basal cell carcinoma and squamous cell carcinoma, ranks as the fifth most common cancer globally, with roughly 1.2 million new cases and 69,000 deaths estimated in 2022. Australia leads the world in age-standardized incidence at 140.1 cases per 100,000 inhabitants, while the absolute burden of cases concentrates in Northern America and Europe. Melanoma, though less frequent and ranking 17th among incident cancers, remains one of the most aggressive malignancies, arising from melanocytes and marked by a heightened capacity for invasion and metastasis. Notably, recent global estimates indicate that absolute deaths from non-melanoma skin cancer now exceed those from melanoma, at approximately 63,000 versus 57,000 worldwide, a trend that underscores the often-underestimated burden of these tumors and their more aggressive subtypes.

The review’s central hypothesis links sleep and circadian health to skin cancer defense. Melatonin synthesis is strictly governed by the suprachiasmatic nucleus, the master circadian clock, which lifts its inhibition of the pineal gland only after dusk. When sleep is disrupted or artificial light floods the night, melatonin production falls, and with it a cascade of cutaneous protections. The authors argue that this circadian-regulated hormone acts as a physiological safeguard for the skin, and that its decline, commonly seen in people with sleep disorders and in the elderly, may impair immune surveillance and facilitate tumor progression. Epidemiological and experimental evidence supports the broader premise: simulated night shifts in humans disrupted the rhythmic expression of DNA repair genes and increased sensitivity to DNA damage, while clock proteins such as CLOCK, BMAL1, PER, and CRY have been shown to coordinate DNA repair, cell cycle control, and programmed cell death.

The molecular detail is where the review becomes particularly compelling. In human keratinocytes, melatonin and its metabolites acted on the earliest consequences of UVB irradiation, countering oxidative and nitrosative stress, shoring up antioxidant defenses, and reducing the formation of DNA photoproducts, with increased phosphorylation of the tumor suppressor p53 supporting a role in DNA damage signaling and repair. In melanocytes, protection ran through the NRF2 pathway: melatonin boosted expression of this master antioxidant regulator, and when researchers silenced NRF2, the hormone’s defensive effect against UVB-induced oxidative damage largely vanished. Mouse studies add a striking temporal dimension. When animals were chronically exposed to UVB at a time of low DNA repair activity, they developed skin tumors earlier and harbored more invasive squamous cell carcinomas than mice exposed at a time of high repair capacity. Human skin, too, shows time-of-day variation in UVB-induced erythema and p53 activation.

Beyond DNA repair, melatonin appears to interfere with the signaling cascades that keep cancer cells alive and proliferating. In B16F10 melanoma cells, the hormone combined with endoplasmic reticulum stress to reduce cell survival through interference with the PI3K/Akt/mTOR pathway, a central growth-signaling axis. Melatonin also reshapes mitochondrial function, reducing oxidative phosphorylation, ATP production, and mitochondrial membrane potential while amplifying reactive oxygen species and proton leak, metabolic shifts that can push cells toward intrinsic apoptosis. Intriguingly, when paired with BRAF and MEK inhibitors, the standard targeted therapies for BRAF-mutated melanoma, melatonin may enhance treatment efficacy by suppressing MAPK signaling and promoting mitochondria-mediated cell death. The hormone also modulates pigmentation, with its metabolite 5-methoxytryptamine enhancing tyrosinase activity and melanogenesis in melanoma cells, a response thought to provide a physical shield against ultraviolet radiation.

The evidence, however, is not uniformly encouraging, and the review is candid about the caveats. Melatonin’s actions are strongly dose-dependent and context-dependent. At physiological concentrations, the hormone is associated with reduced oxidative stress and preserved mitochondrial function, but at supraphysiological levels it can induce reactive oxygen species accumulation, mitochondrial dysfunction, DNA damage, and apoptosis in both malignant and non-malignant skin cells. In one comparative study, high concentrations proved even more cytotoxic to normal fibroblasts than to carcinoma cells, suggesting a limited therapeutic window. Some melanoma cell lines, such as MNT-1, resisted significant growth inhibition altogether, and early clinical observations of high-dose melatonin in advanced melanoma, which reported partial responses and disease stabilization, came from small, non-randomized studies without matched controls, limiting their interpretability.

Pharmacokinetics present another hurdle for systemic use. Oral melatonin is rapidly absorbed, peaks in plasma within 30 to 60 minutes, and is cleared with a half-life of less than an hour, while extensive first-pass hepatic metabolism drives low and highly variable bioavailability. Plasma concentrations achieved in vivo typically fall in the pico- to nanomolar range, far below the supraphysiological levels used in many laboratory experiments. The authors argue that this makes topical delivery the more rational route for skin protection. Melatonin’s low molecular weight and moderate lipophilicity facilitate penetration through the stratum corneum, and topically applied hormone accumulates in epidermal and adnexal compartments, forming a local reservoir that sustains antioxidant and cytoprotective activity without systemic exposure. The molecule even absorbs UVB radiation directly, in the 280 to 320 nanometer range, adding a physical photoprotective component to its biochemical ones.

Human data on topical melatonin, though preliminary, are intriguing. Applied before UV exposure, it reduced UVB-induced erythema in a dose-dependent manner, and under natural sunlight only a 12.5 percent cream showed significant protection compared with placebo and untreated skin. Formulation studies have explored melatonin-based emulsions combined with physical UV filters and high sun protection factors, though the hormone’s sensitivity to light and oxidation demands carefully optimized vehicles to preserve bioactivity. On the therapeutic side, a Cochrane systematic review found that melatonin used alongside standard anticancer therapy probably reduced treatment-related fatigue and nausea, though certainty of evidence for survival and quality-of-life outcomes remains low. Experimental work in hepatocellular carcinoma models further suggests the hormone can suppress PD-L1 expression and enhance the efficacy of immune checkpoint inhibitors, a finding the authors flag as promising but not yet tested in skin cancer.

Older adults emerge as a particularly relevant population, since skin cancer incidence rises with age precisely as endogenous melatonin production declines. Yet aging skin may not respond uniformly to supplementation. An in vitro study documented an age-associated reduction of MT1 receptor expression in human dermal fibroblasts, and knocking down that receptor increased oxidative stress and UV-induced DNA damage, implying that receptor decline could blunt photoprotective responses. Still, an ex vivo study of aged human eyelid skin from donors aged 49 to 77 found that melatonin modified selected aging markers, including Matrix Metalloproteinase 1 expression, suggesting that aged skin retains at least selective responsiveness to the hormone.

The authors are careful to frame their conclusions as a hypothesis rather than a prescription. Most supporting data derive from preclinical models, human studies specifically designed for skin cancer prevention or treatment remain scarce, and no large randomized controlled trials have evaluated melatonin either as a preventive agent in high-risk populations or as an adjuvant in established melanoma and non-melanoma skin cancer. Timing matters as well: because DNA repair is rhythmically regulated, exogenous melatonin taken at the wrong circadian phase could theoretically disrupt endogenous clock dynamics and even increase UV sensitivity. If future research validates the hypothesis, however, the implications could extend beyond any pill or cream, pointing toward the preservation of biological rhythms and restorative sleep as genuine components of cancer prevention. For now, melatonin remains a molecule of remarkable biological plausibility awaiting its clinical trial moment in dermatologic oncology.

Subject of Research: The potential role of melatonin in the prevention and adjuvant treatment of skin cancer

Article Title: Could the use of melatonin be a promising complementary strategy in the prevention of skin cancer?

Article References: Altenfelder, L. A., Xerfan, E. M. S., Tufik, S., & Andersen, M. L. (2026). Could the use of melatonin be a promising complementary strategy in the prevention of skin cancer?. Archives of Dermatological Research, 318(1), Article 510. https://doi.org/10.1007/s00403-026-04933-9

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04933-9

Keywords: melatonin, skin cancer, melanoma, circadian rhythm, oxidative stress, UV radiation, DNA repair, p53, NRF2, topical melatonin, chemoprevention, sleep disorders