The review, conducted according to PRISMA 2020 guidelines and registered in PROSPERO, searched Web of Science, PubMed and EbscoHost for studies published between February 2020 and January 2026. From 404 initial records, 24 studies met the strict eligibility criteria: three addressed primary prevention, meaning measures that stop the disease from developing, and 21 addressed secondary prevention, meaning screening and early detection. The studies spanned North America, Europe and Asia and included one randomized controlled trial, nine diagnostic accuracy studies, thirteen conventional observational studies and one quality improvement study. Quality was assessed with established tools including the Cochrane Risk of Bias 2.0 instrument, the Newcastle-Ottawa Scale and QUADAS-2, and the certainty of the evidence was graded using the GRADE framework.

The epidemiological backdrop gives the work its urgency. According to the Global Cancer Observatory, more than 330,000 new cases of cutaneous melanoma were reported in 2020, with nearly 59,000 deaths, translating into a mortality rate of 17.7 percent. Incidence is rising by 3 to 7 percent each year, doubling every 10 to 20 years, and the International Agency for Research on Cancer predicts an increase of more than 50 percent in new annual cases between 2020 and 2040. Fair-skinned populations in high-UV regions such as Australia, Europe and North America carry the greatest burden, and ultraviolet radiation, particularly intense intermittent exposure, remains the dominant external risk factor, driving the DNA damage and oncogenic mutations, including BRAF and NRAS alterations, that underpin melanomagenesis.

On the primary prevention front, the pickings were slim but intriguing. Two observational analyses of extended follow-up from a large Australian randomized trial, involving 19,114 participants, examined whether daily 100-milligram aspirin could prevent melanoma. In hypertensive individuals, aspirin use was associated with a 27 percent reduction in melanoma incidence, with a hazard ratio of 0.73, and the effect was strongest among those with uncontrolled hypertension. Yet in older participants overall, the same dataset showed no statistically significant benefit, with a hazard ratio of 1.04. The reviewers graded this evidence as low certainty, noting that both analyses come from the same research group and that aspirin carries well-known bleeding risks, so no clinical recommendation can be made until large, independent randomized trials clarify the risk-benefit balance.

The third primary prevention study, from Greece, took a different angle, examining total body nevus counts in 813 people. It confirmed that mole counts decline with age, with people over 51 having a 73 percent lower likelihood of carrying 30 to 60 nevi, and that taller individuals showed a steeper decline, particularly women. The finding hints at genetic mechanisms governing nevus dynamics, echoing genome-wide association work that has identified dozens of loci linking nevus count to melanoma susceptibility. Notably, the search found no new studies on sunscreen formulation or photoprotection during the review window, suggesting that after decades of successful sun-safety campaigns, research energy has migrated decisively toward early detection technology.

That migration is most visible in the eight studies evaluating artificial intelligence for melanoma detection. The review organized these tools into three generations. Classical machine learning, including support vector machines and random forests, requires experts to manually define image features. Deep learning, built on convolutional neural networks such as DenseNet and EfficientNet, learns features automatically from large labeled image sets. The newest approach, self-supervised learning, needs no labeled data at all: in a Swiss study, a self-supervised system combining object detection with vision transformers achieved 95 percent sensitivity in flagging suspicious lesions, and raised the sensitivity of medical students from roughly 63 to 68 percent up to 81 to 82 percent, matching expert dermatologists at 100 percent agreement.

Across the AI studies, specificity ranged from 70.4 to 100 percent, often matching that of specialists, but sensitivity varied widely, from 58.3 percent in two-dimensional total body photography systems to 89 percent in dermoscopic models. Three-dimensional convolutional neural networks outperformed their two-dimensional counterparts, and combining dermatologist judgment with 3D analysis improved accuracy further. Yet the review flagged consistent caveats: consumer-facing smartphone apps underperformed tools embedded in clinical settings with professional oversight; performance dropped in difficult areas such as tattoos, skin folds and hairy regions; and nearly all studies enrolled predominantly fair-skinned, Fitzpatrick type I and II patients, leaving darker phototypes dangerously underrepresented. The reviewers also raised an environmental concern, noting that the energy and water consumption of training self-supervised systems at community screening scale could be unsustainable.

Beyond AI, conventional secondary prevention showed real-world value. A five-year screening initiative in a large US health system, covering nearly 600,000 patients, diagnosed significantly more thin melanomas, those measuring 1 millimeter or less, among screened patients, while thick lesions trended downward. Free beachside screening events in Rhode Island achieved a number needed to screen of just 18.3. Longitudinal surveillance of melanoma-prone families reduced mean tumor thickness at diagnosis from 1.1 to 0.6 millimeters, with 83 percent of prospectively detected tumors classified as early-stage T1 versus 40 percent before the program. Remote training in skin self-examination proved as effective as in-person instruction in a randomized trial of 341 melanoma survivors and their partners, and community pharmacy-based teledermatology in Spain achieved more than 85 percent diagnostic accuracy on submitted photographs, opening a low-threshold referral route for the public.

Two emerging technologies rounded out the review. Hyperspectral imaging paired with deep learning distinguished melanoma from benign nevi with 98 percent accuracy using two-dimensional spectral-spatial data, exploiting spectral differences concentrated in the 500 to 675 nanometer band. Even more futuristic is a wearable microneedle patch developed in China, studded with hundreds of tiny tips and gold-silver nanospheres, that measures tyrosinase, the rate-limiting enzyme of melanin synthesis, directly within suspicious skin lesions using surface-enhanced Raman spectroscopy, with an ultralow detection limit of 0.01 units per milliliter. Because tyrosinase activity is elevated in malignant melanocytes, the reviewers suggest this painless biosensor could one day offer an objective, early biomarker, provided it remains affordable and accurate over time.

The overall message is one of cautious optimism. Advanced imaging combining three-dimensional total body photography, digital dermoscopy and reflectance confocal microscopy currently carries the highest certainty of evidence for early diagnosis, but demands specialist infrastructure. AI tools are sensitive but not yet specific enough, and must be validated across all skin tones before widespread deployment. Aspirin remains a hypothesis, not a prescription. What the review makes clear is that the future of melanoma prevention will likely be hybrid: sun protection and expert-led examination as the foundation, augmented by algorithms, biosensors and genomics, always under the supervision of dermatologists, to catch the world’s deadliest skin cancer while it is still thin, treatable and curable.

Subject of Research: Primary and secondary prevention strategies for cutaneous melanoma, including AI-based screening, chemoprevention and emerging biomarkers

Article Title: New Primary and Secondary Prevention Measures for Cutaneous Melanoma: A Systematic Review

Article References: Palau–del–Valle, M., Bendala–Tufanisco, E., & López–Ruiz, M. A. (2026). New Primary and Secondary Prevention Measures for Cutaneous Melanoma: A Systematic Review. Cancer Reports, 9(10), Article e70698. https://doi.org/10.1002/cnr2.70698

Image Credits: AI Generated

DOI: 10.1002/cnr2.70698

Keywords: cutaneous melanoma, systematic review, artificial intelligence, screening, aspirin chemoprevention, tyrosinase biosensor, total body photography, dermoscopy, UV radiation, early detection, convolutional neural networks, public health

Cutaneous melanoma is the most lethal and aggressive cancer of the skin, arising from malignant transformation of melanocytes and marked by rapid proliferation, high metastatic potential, and notorious resistance to conventional therapies. The latest epidemiological estimates from the International Agency for Research on Cancer counted 331,722 new cases and 58,667 deaths worldwide in 2022, and even as targeted therapies and immunotherapies have transformed the landscape, low response rates and acquired resistance continue to frustrate effective management. That unmet need is precisely why the study’s authors turned their attention to two signaling systems increasingly recognized as vulnerabilities in tumors: purinergic signaling, the extracellular communication network built on adenosine triphosphate and its breakdown products, and the inflammatory axis involving interleukin-6 and the NLRP3 inflammasome.

Purinergic signaling, first proposed in 1972, operates through P1 and P2 receptors that respond to a ladder of molecules: ATP, adenosine diphosphate, adenosine monophosphate, and adenosine. Depending on which molecules dominate the extracellular space, the same pathway can drive cell proliferation or push a cell toward apoptosis. In the tumor microenvironment, the balance tilts dangerously. Extracellular adenosine, generated in abundance, acts as a potent immunosuppressant, blunting the anti-tumor immune response. The levels of these signaling molecules are controlled largely by ectonucleotidases, membrane-bound enzymes known as CD39 and CD73, along with adenosine deaminase, which breaks adenosine down into inosine. CD39 converts ATP into ADP and AMP; CD73 then hydrolyzes AMP into adenosine. Overexpression of CD73 has been documented in pancreatic adenocarcinoma, thyroid cancer, and melanoma itself, and both CD39 and CD73 have been flagged as next-generation checkpoint targets for cancer therapy.

Against that backdrop, calcitriol offered an intriguing candidate. Previous work had shown that 1-alpha,25-dihydroxyvitamin D3 induces apoptosis in melanoma cells, enhances the anticancer effects of classical chemotherapy, inhibits proliferation and migration in breast cancer models, and can modulate IL-6 expression. Yet its mechanism of action on the purinergic system in melanoma had never been systematically explored. The research team hypothesized that calcitriol exerts a potent antineoplastic effect on cutaneous melanoma by modulating the activity and expression of ectonucleotidases, thereby rewiring the extracellular nucleotide landscape in favor of tumor cell death.

To test the hypothesis, the investigators cultured two human cutaneous melanoma cell lines, A375 and SK-MEL-28, treating them with calcitriol at 1, 10, and 50 nanomolar concentrations for 24 hours. The A375 line, which displays epithelial morphology and an invasive, metastatic profile, and SK-MEL-28, a polygonal melanoma line, were subjected to a battery of assays: MTT and fluorescence microscopy viability tests, measurements of mitochondrial transmembrane potential using the TMRE dye, detection of apoptotic bodies by acridine orange staining, wound-healing migration assays, and enzymatic quantification of ATP, ADP, and AMP hydrolysis alongside adenosine deaminase activity. Gene expression of CD39, CD73, IL-6, and NLRP3 was assessed by RT-qPCR, normalized to the housekeeping gene GAPDH and analyzed with the comparative delta-delta-CT method, with one-way ANOVA and Dunnett’s post hoc test applied throughout.

The results were striking and, in one respect, unexpectedly selective. In A375 cells, calcitriol significantly reduced viability at every concentration tested, with the MTT assay yielding P values of 0.0004 at 1 nM and below 0.0001 at 10 and 50 nM. Fluorescence microscopy independently corroborated the viability loss across all doses. Crucially, the treatment also collapsed the mitochondrial transmembrane potential of A375 cells at all concentrations, with statistical significance reaching P < 0.0001, a disruption consistent with the initiation of intrinsic apoptosis. Matching that mitochondrial signature, the treated cells showed marked nuclear fragmentation: apoptotic bodies rose significantly at all three doses, while cell counts fell in a dose-dependent manner. Wound-healing assays added another dimension, revealing that calcitriol inhibited A375 migration and wound closure at every concentration tested within just 24 hours, with P < 0.0001, a finding with obvious implications for blocking metastasis.

The SK-MEL-28 line told a different story. Calcitriol produced no significant reduction in its viability and left its mitochondrial potential untouched; at 1 nM, viability even increased slightly. The researchers point to a well-documented explanation: SK-MEL-28 cells express functionally lower levels of the vitamin D receptor than several other melanoma lines, rendering them resistant to calcitriol’s antiproliferative effects at nanomolar concentrations, with prior studies noting sensitivity only at much higher doses. The contrast between the two cell lines underscores that calcitriol’s anticancer activity depends on functional vitamin D receptor signaling, a caveat that will shape which patients might ultimately benefit from a calcitriol-based adjuvant strategy.

The deepest technical insight, however, came from the purinergic analysis. Calcitriol left ATP hydrolysis unchanged but significantly decreased ADP hydrolysis at 1 and 10 nM, with a modest increase at 50 nM, and reduced AMP hydrolysis at 10 and 50 nM. Because CD39 and CD73 jointly convert ATP down the cascade to adenosine, dampened AMP breakdown means less substrate for adenosine production. Consistent with that logic, adenosine deaminase activity, which depends on adenosine availability, dropped sharply at 10 and 50 nM. At the gene level, calcitriol downregulated CD39 expression at 10 and 50 nM and exerted a strong suppressive effect on CD73 at those same concentrations, P < 0.0001. Together, these changes describe a coherent suppression of the AMP-to-adenosine axis, the very pathway tumors exploit to generate immunosuppressive adenosine in their microenvironment. By throttling adenosine generation, calcitriol may indirectly loosen the tumor’s grip on local immunity.

The inflammatory arm of the study completed the picture. Extracellular nucleotide signaling is intimately connected to inflammation, and both IL-6 and NLRP3 have dual, sometimes controversial roles in cancer, with evidence linking them to tumor progression, chemoresistance, immune cell infiltration, and poor prognosis in melanoma. Calcitriol significantly downregulated IL-6 expression at 10 nM and 50 nM, and produced an equally robust reduction in NLRP3 gene expression, with P < 0.0001 at both doses. Given that IL-6 targeting has been proposed to abrogate melanoma growth and progression, and that NLRP3 is increasingly viewed as a therapeutic target capable of reducing chemoresistance, these transcriptional effects suggest calcitriol acts on multiple fronts at once: killing tumor cells directly, impairing their migratory capacity, starving the immunosuppressive adenosine pathway, and calming the pro-tumoral inflammatory circuitry.

The authors are careful about scope. Their analysis covered gene expression rather than protein levels, and only two cell lines were examined, which they acknowledge as a limitation given the distinct metabolic profiles of A375 and SK-MEL-28. They also stress that while the nanomolar concentrations used appear practical for in vivo applications, safety testing is required, and future animal studies should monitor calcium levels to guard against hypercalcemia, the classic toxicity of active vitamin D compounds. Encouragingly, the adjuvant concept already has clinical footprints: calcitriol has been shown to enhance the effects of cisplatin and dacarbazine in melanoma cells, to combine favorably with the VEGFR inhibitor Cediranib, and, in a prospective phase Ib study, to be well tolerated in metastatic melanoma patients receiving high-dose encapsulated calcitriol alongside temozolomide, with no significant secondary side effects reported. Combined with prior evidence that calcitriol can sensitize melanoma cells to proton beam irradiation, the new purinergic mechanism adds a mechanistic rationale to an accumulating clinical case. If subsequent in vivo work confirms that calcitriol’s ectonucleotidase modulation translates into restored anti-tumor immunity, the sunshine vitamin’s most potent form could find itself written into the melanoma treatment algorithm.

Subject of Research: Antineoplastic effects of calcitriol on cutaneous melanoma cells via purinergic signaling modulation

Article Title: Calcitriol, the active form of vitamin D, induces cell death and purinergic signaling modulation in cutaneous melanoma cells

Article References: da Silva, G. B., Narzetti, R. A., Dallagnol, P., Ozelame, B. C., Manica, D., Ramos, V. H. M., Kempka, A. P., & Bagatini, M. D. (2026). Calcitriol, the active form of vitamin D, induces cell death and purinergic signaling modulation in cutaneous melanoma cells. Medical Oncology, 43(10), Article 288. https://doi.org/10.1007/s12032-026-03412-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03412-5

Keywords: calcitriol, vitamin D, cutaneous melanoma, purinergic signaling, ectonucleotidases, CD39, CD73, apoptosis, mitochondrial membrane potential, IL-6, NLRP3, adjuvant therapy