Translate this page into:
Navigating the pharmacological landscape of ultraviolet-induced mutations in skin carcinogenesis
, Sharon Philip Jain2, Filiza Koya1, Syed Aasim Syed Nasir1, Rabab Hunaid Abbas1,
*Corresponding author: Rabab Hunaid Abbas, Department of Medicine, Tbilisi State Medical University, Tbilisi, Georgia. rabababbas2002@gmail.com
-
Received: ,
Accepted: ,
How to cite this article: Mohammed Saleem S, Philip Jain S, Koya F, Syed Nasir S, Hunaid Abbas R. Navigating the pharmacological landscape of ultraviolet-induced mutations in skin carcinogenesis. CosmoDerma. 2025;5:73. doi: 10.25259/CSDM_60_2025
Abstract
Ultraviolet (UV) radiation is a known environmental carcinogen whose adverse effects continually contribute to the global burden of disease. One of its brutal effects manifests in the form of skin cancers – namely, basal cell carcinoma, squamous cell carcinoma, and melanoma, its more aggressive but rare counterpart. UV rays exert their effect by direct deoxyribonucleic acid (DNA) damage, diminishing the body’s natural protective repair mechanisms, paving the way for transforming healthy cells into cancerous ones and increasing their metastatic potential. This includes the transformation of typically protective melanin from an antioxidant to a pro-oxidant, inducing oxidative stress and leading to DNA damage in melanocytes. This damage disrupts key signaling pathways such as mitogen-activated protein kinase (MAPK), B-raf proto-oncogene, serine/threonine kinase (BRAF), rat sarcoma viral oncogene homolog (RAS), contributing significantly to melanoma genesis. Treatment strategies target elements involved in these pathways by different mechanisms, such as boosting immune cell components, inducing programmed cell death (apoptosis), inhibiting DNA synthesis pathways, and halting tumor progression, to name a few. The use of novel drugs that target the melanocortin-1 receptor pathway, toll-like receptor 4, and non-coding ribonucleic acid, as well as innovative therapies such as photodynamic therapy, reflects advancements in skin cancer treatment. The prevalence of melanoma steadily rises annually, prompting newer and more targeted approaches to medicine and education regarding skin protection. This literature review summarizes current knowledge regarding pharmacological approaches to skin cancer, focusing on complex molecular mechanisms affected by UV-induced damage. Rising prevalence and advancements in treatment modalities have warranted attention on this topic.
Keywords
Pathogenesis
Skin cancer
Therapy
Ultraviolet radiation
INTRODUCTION
Skin cancers have become a major global health concern that affects individuals of all age groups. A significant factor linked to keratinocyte cancer is exposure to ultraviolet radiation (UVR) all over the world.[1] In countries like India, the major concern of skin cancers is said to be exposure to arsenic (As). The main way that humans are exposed to As is by consuming water. Skin malignancies which include Bowen’s disease (As-BD, carcinoma in situ), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) have all been related to this exposure.[2] According to the World Health Organization, over 1.5 million cases of skin cancer were documented worldwide in 2022,[3] indicating its prevalence across all continents. The primary types are melanoma and non-melanoma skin cancers (NMSC). NMSC is further categorized into BCC, SCC, and actinic keratosis (AK).[4,5] This study has explored their patterns, revealing that melanoma and BCC are predominantly associated with sunburns, whereas SCC is more closely linked to work-related sun exposure over a lifetime.[5] Other types include Merkel-cell carcinoma and Kaposi sarcoma (KS). The spectrum of harmful radiations includes electromagnetic waves emitted between 200 and 400 nm, with ultraviolet (UV)B wavelengths between 290 and 320 nm posing the highest risk.[6]
The worldwide age-standardized rate for melanoma is 3.7% for males and 2.9% for females, NMSC (BCC and SCC) – 14.0% in males and 7.5% in females, and KS-0.6% in males and 0.3% in females.[7] [Figure 1] points out the comparison between males and females according to the 2022 statistics. NMSCs account for approximately 1–2% of all skin tumors in the Indian population. Among these, SCC makes up about 30–65% of cases, while BCC comprises around 20–30%.[8] Comparing India’s skin cancer prevalence with that of other parts of the world, it is low relative to all kinds of cancers. The northern region of India is where the greatest incidence of melanoma and NMSCs among Indian males are found. In the Indian population, exposure to PUVA (psoralen and UV A treatment) and having fair skin seem to be the main causes of skin cancer incidence.[9] Melanin synthesis by melanocytes is important for skin pigmentation. Carcinogenesis begins when melanin’s antioxidants transform into prooxidants on exposure to UVR, X-rays, and heavy metals. Oxidative stress harms melanocyte deoxyribonucleic acid (DNA), forming mutations that trigger aberrant signaling pathways. p53, TERT, BRAF, RAS, and MPK genes are often mutated, causing abnormal cellular functions leading to cancer development.[10] Genomic changes are essential to the development of melanoma. The BRAF V600E, the most common BRAF mutation, is present in about 80% of patients, 15% had neurofibromin 1 (NF1) mutations, while 20% had NRAS mutations. Moreover, 15–20% have KIT proto-oncogene, receptor tyrosine kinase (KIT) mutations, 5% have rac family small GTPase 1 (RAC1) mutations, and 78% have telomerase reverse transcriptase (TERT) promoter mutations.[11] The data in [Figure 2] summarizes the epidemiological prevalence of these melanoma mutations. Understanding the landscape of these mutations is essential, due to their dual role as diagnostic markers and targets for personalized treatment approaches. Understanding the landscape of these mutations is essential, due to their dual role as diagnostic markers and targets for personalized treatment approaches.
- Percentage distribution of skin cancer cases by gender. NMSC: Non-melanoma skin cancers, KS: Kaposi sarcoma.
- Percentage of common genetic mutations in melanoma. BRAFV600E: B-raf proto-oncogene, serine/threonine kinase - V600 mutation, KIT: KIT proto-oncogene, receptor tyrosine kinase, TERT: Telomerase reverse transcriptase, NRAS: Neuroblastoma RAS viral oncogene homolog, RAS: Rat sarcoma genes, NF1: Neurofibromin 1, RAC1: Rac family small GTPase 1.
METHODOLOGY
Papers published between August 2019 and August 2024 were analyzed across databases such as Google Scholar and PubMed using keywords such as UVR, skin cancer, therapy, and pathogenesis, and 41 papers were selected for this literature review.
RESULTS
With rising trends in skin cancer, it has become important to invest our resources toward new and better treatment modalities. This review provides a comprehensive evaluation by focusing on a deeper molecular understanding of mechanisms of dermatological carcinogenesis, summarizing existing treatment strategies, recommending ideas for future trials, and outlining preventive measures that can be taken to mitigate the risk of carcinogenesis [Table 1].
| Cause | Mechanism involved | Targeted Treatment/Preventive Strategies |
|---|---|---|
| MC1R Pathway | The MC1R plays a role in melanomagenesis. Defects lead to mutations and activation of BRAF in MAPK or PI3K-Akt pathways. | Drugs like PLX4032 and Buparlisib target MAPK and PI3K/PTEN pathways effectively. Combined use reduces resistance in melanoma treatment. |
| Role of Melanin | Melanin can contribute to cancer through chemiexcitation, generating free radicals leading to DNA damage. | Theaflavin, an antioxidant, reduces UV damage, inhibits tyrosinase activity, and can be used in sunscreens, showing potential in preventing skin cancer. |
| HPV | HPV, particularly beta HPV, causes skin cancer through E6 and E7 proteins that disrupt tumor suppressor genes, especially TP53. | HPV vaccines may reduce skin cancer risk by targeting the oncogenic effects of HPV in skin carcinogenesis. |
| ncRNAs | ncRNAs drive the expression of pro-inflammatory cytokines and microRNAs like miR-21-3p. | Targeting ncRNAs by blocking their interaction with transcription factors or reducing miR-21-3p expression. |
| CXCR2 | Upregulated by UVR, contributes to skin aging, and promotes angiogenesis, supporting tumor growth. | Targeting CXCR2 activity can reduce UV-induced skin damage and improve outcomes for individuals at risk of skin cancer. |
| Diet and UVR: Impact of Lipids | Lipids, like trans-urocanic acid, play roles in UV protection. Unsaturated fats are carcinogenic, while saturated fats are relatively benign. | Dietary supplements rich in omega fatty acids and PAF pathway inhibitors may reduce skin cancer risk while avoiding foods like citrus fruits containing harmful furocoumarins is recommended. |
| NER | NER is crucial in correcting UVR-induced DNA damage. Genetic disorders affecting NER increase skin cancer risk. |
Advances in therapies targeting NER mechanisms offer potential benefits for individuals with impaired DNA repair processes. |
| TLR-4 and Innate Immunity | TLR-4 activation by UVR leads to disrupted DNA repair and immunosuppression, promoting tumorigenesis. | TLR-4 antagonists like Resatorvid and nutraceuticals such as spirulina show potential in preventing and treating skin cancer. |
| Atg7gene | Atg7 regulates autophagy and apoptosis, with UVR triggering pro-inflammatory cytokine production, contributing to tumorigenesis. | PDT, which induces apoptosis via oxidative stress, is a promising treatment for skin cancer, especially when combined with self-assembling peptides for enhanced efficacy. |
| Mast cells | Mast cells release inflammatory mediators upon UV exposure, contributing to skin alterations and potential skin cancer development. | Mast cell stabilization with drugs like ketotifen reduces UV-induced skin changes, indicating a therapeutic approach for preventing skin damage. |
| TGF-β | TGF-β, upregulated by UVR, promotes skin cancer progression and angiogenesis, often involving mutations in tumor suppressor genes like TP53. | Combining TGF-βinhibitors with immune checkpoint inhibitors, such as M7824 or LY2157299 with anti-CTLA-4 antibodies, enhances cancer. |
| Galectin | Galectin, involved in apoptosis and T-cell regulation, is associated with increased susceptibility to aggressive cancers, including skin cancer. | Anti-galectin therapies, including monoclonal antibodies like LYT200 and galectin-specific siRNA-loaded nanoparticles, show potential in targeting galectin for treatment. |
MC1R: Melanocortin-1 receptor, HPV: Human papillomavirus, DNA: Deoxyribonucleic acid, UV: Ultraviolet, UVR: Ultraviolet radiation, ncRNAs: Non-coding ribonucleic acids, NER: Nucleotide excision repair, TGF-α: Transforming growth factor-alpha, IL: Interleukin, PDT: Photodynamic therapy, TLR-4: Toll-like receptor 4, PAF: platelet-activating factor, siRNA: Small interfering ribonucleic acid, MAPK: Mitogen-activated protein kinase, PI3K: Phosphoinositide 3-kinase, PTEN: Phosphatase and tensin homolog; tumor suppressor, BRAF: B-raf proto-oncogene, serine/threonine kinase, CXCR2: C–X–C motif chemokine receptor 2, CTLA-4: Cytotoxic T-lymphocyte-associated protein 4.
The melanocortin-1 receptor (MC1R) pathway
Melanoma genesis – synthesis of melanin by melanocytes is significantly influenced by the MC1R. It controls cellular proliferation, skin pigmentation, and the type of melanin generated. UVR stimulates MC1R and raises alpha-melanocyte stimulating hormone (α-MSH) expression. [6] On activation, BRAF participates in the phosphoinositide 3-kinas- protein kinase B (PI3K-Akt) or MAPK signaling pathways. In addition, this kinase enzyme is continuously activated due to an oncogenic mutation that replaces glutamic acid with valine. As per clinical studies, PLX4032 and buparlisib drugs targeting the MAPK and PI3K/phosphatase and tensin homolog (PTEN) pathways are useful in treating melanomas.[12,13] The combination effectively reduces the development of resistance compared with monotherapy.[6] According to research in animals, melanoma is avoided by palmitoylation-induced MC1R activation.[14] In addition, long-term UV-B exposure activates the Akt pathway, triggering inflammatory pathways that aid in tumorigenesis. Apigenin has been discovered to reverse these alterations by reducing mammalian target of rapamycin (mTOR) activity, increasing autophagy, and blocking the Akt pathway, thus preventing the growth of cancerous cells. Apigenin-treated SCC models demonstrated lower cyclooxygenase-2 (COX-2) expression and decreased conversion of microtubule-associated proteins.[15,16] Continued research on the above pathways and their signaling mechanisms can help cure melanoma and promise improved results with combination treatments.
Role of melanin
Melanin, produced by melanocytes, is crucial for skin protection. It is synthesized in melanosomes and transferred to keratinocytes, forming a physical barrier by surrounding the nuclei of keratinocytes, effectively scattering and absorbing UVR. This action reduces the penetration of UV light into deeper skin layers, thereby protecting against UV-induced cellular damage.[17] Despite its protective roles, melanin can also contribute to skin cancer pathogenesis. UVR triggers melanin chemiexcitation, generating harmful free radicals and reactive intermediates, leading to DNA damage, which can then initiate and promote melanoma by influencing pathways involved in tumor initiation, progression, and resistance to therapies.[17] Theaflavin is an antioxidant, providing the benefit of reducing skin damage from UVR and thus preventing skin cancer. It has been proven to inhibit monophenolase and diphenolase activity of the tyrosinase enzyme and block melanin synthesis. The study in Zebrafish determined the sun protection factor (SPF) value of theaflavin as 9.73; suggesting its potential use as a sunscreen agent and incorporation into existing cosmetic products.[18] Continued investigation into its safety and effectiveness could pave the way for skincare and cosmetic products, offering new avenues for skin cancer prevention and care.
Role of human papillomavirus (HPV)
Emerging evidence highlights the significant role of HPV, particularly beta HPV, as a crucial cofactor in skin carcinogenesis. It contributes to the development of skin cancer by producing the oncogenic proteins E6 and E7. Mouse studies have shown that individuals harboring its oncogenic proteins are more likely to develop NMSC after prolonged exposure to UVR, compared to those without them.[19] They undermine tumor suppressor genes by disrupting the function of TP53, a key regulator of DNA replication and apoptosis in mutagenic cells. This disruption creates a favorable environment for carcinogenesis. Notably, the severity of skin lesions is inversely related to viral load, suggesting that HPV’s impact is more pronounced in pre-cancerous lesions.[20] These findings underscore the importance of HPV vaccines as a preventive measure in dermatology, highlighting their potential to reduce the risk of skin cancer by targeting a critical, yet often overlooked factor in its development.
Role of non-coding ribonucleic acids (ncRNAs)
ncRNAs have emerged as critical regulators in the inflammatory and carcinogenic processes underlying skin cancer. These molecules drive the expression of pro-inflammatory cytokines such as transforming growth factor-alpha (TGF-α) and Interleukin (IL)-6, and the pro-inflammatory microRNA miR-21-3p, inhibiting the upregulation of mothers against decapentaplegic homolog 4 (SMAD-4), a crucial negative feedback regulator of TGF-α.[21] HPV exploits these pathways, with its oncoproteins leveraging ncRNAs to facilitate carcinogenesis.[22] Recent advancements in drug development have shown promise in targeting ncRNAs, either by blocking their interaction with transcription factors or reducing miR-21-3p expression. Such strategies have been explored in hepatitis C virus cases and can be a potential therapy in skin cancer management.[21] Continued research into the role of ncRNAs in skin cancer could unveil new therapeutic measures to improve treatment outcomes.
Role of CXCR2
CXCR2 is a receptor for IL-8 and CXCL1, found in various cells, including epithelial cells. The cell type determines if its role in cancer is beneficial or harmful.[23] UVR induces oxidative stress by upregulating CXCR2 and increasing the levels of P21 and P16 proteins. This upregulation contributes to skin aging, such as wrinkles, and promotes angiogenesis, which supports tumor growth. Anti-aging formulas reduce CXCR2, P21, and P16 levels, boosting melanin and moisture content and mitigating UV-induced skin damage.[23] Targeting CXCR2 and its associated pathways offers the potential to prevent and treat skin cancer by potentially reducing UV-induced skin damage.
Diet and UVR: The impact of lipids
Lipids offer valuable insights into the molecular mechanisms underlying skin cancers. Trans-urocanic acid, a byproduct of histidine catabolism, acts as an endogenous sunscreen, mitigating UVR-induced damage. On UVB exposure, it is photoisomerized into cis-urocanic acid, which produces immunomodulatory lipids such as platelet-activating factor (PAF). This conversion triggers the synthesis of anti-inflammatory cytokines and suppresses Tregs and CD4+ T-cell activation, facilitating immune evasion. Research in mice has demonstrated an inverse correlation between low-fat diets and skin cancer risk, highlighting that unsaturated fats are carcinogenic, whereas saturated fats are comparatively benign. These findings suggest the protective role of dietary supplements rich in omega fatty acids and PAF pathway inhibitors in reducing skin cancer incidence, progression, and mortality.[24] Conversely, citrus fruits containing furocoumarins, such as 8-methoxypsoralen and 6’,7’-dihydroxybergamottin, have been shown to enhance the harmful effects of UVR on the skin.[25] Thus, dietary choices and lipid metabolism are critical in skin cancer prevention and progression.
Defective nucleotide excision repair
The intricate mechanisms of DNA repair play a pivotal role in maintaining cellular integrity under UVR stress. UVR exposure induces the dimerization of pyrimidine bases, forming bulky covalent bonds that disrupt normal DNA replication and transcription. The body relies on an intrinsic mechanism known as nucleotide excision repair to rectify these lesions and restore the helical structure of DNA. However, genetic disorders such as Xeroderma Pigmentosa and Cockayne Syndrome, characterized by mutations in this pathway, significantly impair the repair process. Individuals with these conditions are at a heightened risk of developing skin cancer due to their inability to repair UVR-induced DNA damage compared to the rest of the general population. Advances in therapies targeting skin cancer may offer substantial benefits for these individuals, potentially improving their quality of life.[26]
Role of toll-like receptor 4 (TLR-4) in innate immunity
The role of TLR-4 in skin cancer development underscores the complex interplay between innate immunity and carcinogenesis. UVR exposure triggers the formation of pathogen-associated molecular patterns and damage-associated molecular patterns in the skin, leading to elevated TLR-4 expression. This activation subsequently enhances the expression of nuclear factor-kappa B (NF-kB) and activator protein 1, which disrupts DNA repair mechanisms, promotes immunosuppression, and facilitates the accumulation of mutations, thus advancing tumorigenesis. Preclinical studies in melanoma models have demonstrated that TLR-4 antagonists like Resatorvid effectively inhibit tumor growth and showcase their potential in preventing and treating skin cancer, especially for tumors with poor immunogenicity.[27,28] The protective effects of nutraceuticals such as spirulina and soy isoflavones against carcinogenesis are due to inhibition of NADPH oxidase 1 (Nox1)-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and NF-kB transcriptional activity.[29] Understanding the role of TLR-4 in skin cancer and exploring its modulation through targeted therapies and nutraceuticals could lead to novel strategies to enhance overall patient outcomes.
Role of the Atg7 gene
The Atg7 gene plays a critical role in regulating autophagy and apoptosis. Under normal conditions, it regulates these processes to maintain cellular homeostasis. However, UVR exposure triggers Atg7 to produce pro-inflammatory cytokines and increase the expression of prostaglandinendoperoxide synthase/cyclooxygenase-2 (Ptgs2/Cox-2)through cAMP response element-binding protein 1 (CREB1)/CREB and IL1B/IL1β pathways, creating an oxidative stress environment conducive to tumorigenesis.[30] While some studies comparing UVR exposure in wild-type versus Atg7-deleted mice revealed that the latter group exhibited delayed skin tumor formation and a reduced average tumor count, others have demonstrated an increased risk with Atg7 gene deficiency.[30,31] This suggests that Atg7 can be both positively and negatively associated with skin cancer development and selectively targeting its expression may offer a therapeutic approach to skin cancer management. In contrast, photodynamic therapy (PDT), which exploits oxidative stress to induce apoptosis, presents a promising alternative. On light exposure to target cancer cells, PDT generates reactive oxygen species, offering a safer and noninvasive treatment option.[32] Furthermore, combining PDT with self-assembling peptides can enhance targeted delivery and treatment efficacy.[33] The dual role of Atg7 in skin cancer highlights its potential as a therapeutic target, and the innovative possibilities offered by PDT and its combinations warrant further research into these mechanisms.
Role of mast cells
Mast cells release mediators such as histamine and PAF on degranulation, contributing to inflammation. Although the precise mechanisms linking mast cells to UV-induced skin alterations remain inadequately understood, their involvement is suggested by studies where stabilization with ketotifen reduced UV-induced skin changes. An increase in the number of dermal mast cells and their serine proteases has been noted in pre-malignant UV-induced skin lesions. Their role can be influenced by Vitamin D levels, whose deficiency potentially leads to its dysregulated response and altered inflammatory or immunosuppressive behavior.[34] Further investigation into how mast cell stabilization affects UV-induced skin alterations could provide new insights into managing skin damage and its therapeutic role.
Role of transforming growth factor-beta (TGF-β)
UVR increases the expression of TGF-β, resulting in skin cancer progression. This upregulation stimulates the production of various pro-inflammatory cytokines and matrix metalloproteinases and simultaneously causes loss-of-function mutations in its signaling pathways, including the tumor suppressor gene TP53. Its activation leads to neutrophil recruitment, resulting in collagen fibril damage and angiogenesis, changes commonly observed in metastatic cancers.[35] Since immune checkpoint inhibitors alone have proved inadequate for effective cancer treatment, adding TGF-β inhibitors may enhance therapeutic outcomes. Notable advancements include M7824, a bifunctional fusion protein targeting both programmed death-ligand 1 and TGF-β and the combination of LY2157299, a TGF-β blocker with an anti-CTLA-4 antibody has demonstrated promising results in animal studies.[15,36,37] Further exploration of these combined approaches could lead to more effective therapeutic options and better patient outcomes.
Role of galectin
Galectin, a protein that binds β-galactoside sugars, plays a multifaceted role in cellular processes such as apoptosis, autophagy, and the regulation of T-cell activation. Its elevated levels have been associated with several aggressive cancers, including skin cancer. Research comparing mice with over-expressed Gal-7 in skin cells to wild-type mice revealed that the former had an increased susceptibility to dermatologic cancerous lesions, highlighting galectin’s involvement in NMSC.[38] Emerging therapeutic strategies include the development of anti-galectin monoclonal antibodies (mAbs), with ongoing clinical trials assessing the efficacy of anti-GAL9 mAb LYT200. In addition, novel approaches utilizing nanoparticles loaded with galectin-specific small interfering ribonucleic acid show promise in selectively targeting galectin molecules.[39] These advancements emphasize the potential of galectin-targeted therapies in skin cancer treatment, offering hope for more effective and specific anti-cancer interventions. The development of precancerous lesions, such as AK in SCC, often involves the interplay of multiple underlying mechanisms, hence, utilizing a combination of the therapeutic agents discussed above may be necessary for treating advanced cases.[40]
DISCUSSION
UVR enhances the expression of α-MSH and the activity of MC1R, allowing mutations to accumulate. Understanding the intricacies of the MC1R pathway and its associated signaling mechanisms will help us develop targeted skin cancer therapies involving the MAPK and PI3K pathways. Contrary to the popular belief that melanin plays a protective role against skin cancer, we know that it can be harmful as well. Chemiexcitation of melanin produces a proinflammatory environment conducive to tumorigenesis. The development of cosmetics containing novel sunscreen compounds such as theaflavin should be investigated. HPV vaccines, though mainly branded as a prophylactic measure for cervical cancer, the same can also be applied to skin cancers due to similar pathophysiological factors. The role of ncRNAs in skin cancer pathophysiology emphasizes the need for targeted approaches to inhibit their oncogenic effects. Reduced amounts of cytokines generated by T cells, including tumor necrosis factor-alpha, interferon-gamma, IL-2, IL-10, IL-5, and IL-4, have been associated with immunosuppressants in India to As exposure. While a few anti-CXCR2 therapies have been developed, their outcomes have been inconsistent. Further research is required to explore their therapeutic potential, as CXCR2 remains a promising target for skin cancer treatment. Integrating protective dietary supplements and avoiding potentially harmful foods can significantly contribute to reducing skin cancer risk and promoting overall skin health. Enhancing our understanding of nucleotide excision repair mechanisms and developing targeted therapies could significantly mitigate the elevated skin cancer risk in individuals with genetic disorders affecting DNA repair, thereby offering hope for improved management and outcomes. TLR-4 antagonists and nutraceuticals can help modulate innate immunity and suppress the pro-tumorigenic inflammatory environment. The Atg7 gene is a double-edged sword in cancer, acting as both a tumor suppressor by promoting autophagy-mediated cell survival under stress and a tumor promoter by aiding cancer cell resistance to therapy. Given its complex function, further research is crucial to explore how modulating Atg7 could enhance cancer treatment strategies. The role of mast cells in UV-induced skin is not completely understood yet, and it warrants further investigation, as mast cell stabilizers could be possibly used in the management of pre-cancerous lesions. Targeting TGF-β, alongside immune checkpoint inhibitors, presents a promising combination strategy for improving skin cancer treatment. Galectin-based therapies, such as galectin mAbs, show promise for advancing pharmacological approaches in skin cancer management. However, further extensive research is essential to refine their role as adjuncts to surgical treatment for both precancerous and cancerous dermatologic lesions.
CONCLUSION
Skin cancer is mostly caused by UVR, particularly UVB rays, and is worsened by infections such as HPV beta and gene alterations such as BRAF and PTEN. A holistic approach combining prevention, early detection, and efficient treatment is needed to manage this disease and address its rising prevalence. Although eumelanin protects darker skin, skin cancer is not uncommon in some parts of India and the world. In India, the number of cases of SCC and BCC is currently on the rise.
Drugs targeting biochemical pathways such as TGF-β, PI3K, and MAPK are promising treatment modalities, and when combined with traditional treatments, they can greatly enhance outcomes. In melanoma patients, for example, it has been discovered that combining BRAF inhibitors with mitogen-activated protein kinase kinase (MEK) inhibitors lowers resistance and produces longer-lasting effects. Furthermore, diets rich in omega-3 and antioxidant-rich foods help decrease the risk and progression of skin cancer, which could improve the efficacy of medication treatments. Photodynamic treatment is another cutting-edge strategy that uses light to activate photosensitizing chemicals, specifically killing cancer cells. Combining PDT, which is non-invasive, is appropriate for people who are unable to tolerate harsh operations.
Topical treatments such as anti-aging lotions lessen the impact of UVR and help prevent skin cancer. They frequently include substances such as COX-2 and CXCR2 inhibitors, targeting processes connected to cancer development. Incorporating these substances into regular skincare regimens may lower the risk of skin cancer and precancerous lesions. These tactics are being improved by ongoing research, which highlights how crucial it is to include fresh perspectives in clinical practice. The burden of skin cancer could be decreased globally, and patient outcomes greatly enhanced by combining cutting-edge therapies with conventional therapy and preventative measures.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent was not required, as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
References
- Mechanisms of UV-induced mutations and skin cancer. Genome Instab Dis. 2020;1:99-113.
- [CrossRef] [PubMed] [Google Scholar]
- Immunological dysfunction in chronic arsenic exposure: From subclinical condition to skin cancer. J Dermatol. 2018;45:1271-7.
- [CrossRef] [PubMed] [Google Scholar]
- Ultraviolet radiation. 2016. Geneva: World Health Organization; Available from: https://www.who.int/news-room/fact-sheets/detail/ultraviolet-radiation [Last accessed on 2024 Aug 14]
- [Google Scholar]
- The epidemiology of skin cancer worldwide In: Skin cancer: Pathogenesis and diagnosis. Germany: Springer Nature; 2021. p. :69-77.
- [CrossRef] [Google Scholar]
- Vascular endothelial growth factor as an immediate-early activator of ultraviolet-induced skin injury. Mayo Clin Proc. 2022;97:154-64.
- [CrossRef] [PubMed] [Google Scholar]
- Ultraviolet radiation and melanomagenesis: From mechanism to immunotherapy. Front Oncol. 2020;10:951.
- [CrossRef] [PubMed] [Google Scholar]
- Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63.
- [CrossRef] [PubMed] [Google Scholar]
- Indian journal of dermatopathology and diagnostic dermatology. Available from: https://journals.lww.com/ijdd/fulltext/2014/01020/nonmelanoma-skin-cancers-an-indian-perspective.1.aspx [Last accessed on 2025 May 22].
- [CrossRef] [Google Scholar]
- Incidence of melanoma and nonmelanoma skin cancers in Indian and the global regions. J Cancer Res Ther. 2021;17:906-11.
- [CrossRef] [PubMed] [Google Scholar]
- Aetiology and pathogenesis of cutaneous melanoma: Current concepts and advances. Int J Mol Sci. 2021;22:6395.
- [CrossRef] [PubMed] [Google Scholar]
- A narrative review of current knowledge on cutaneous melanoma. Clin Pract. 2024;14:214-41.
- [CrossRef] [PubMed] [Google Scholar]
- Melanoma brain metastases: Biological basis and novel therapeutic strategies. Exp Dermatol. 2022;31:31-42.
- [CrossRef] [PubMed] [Google Scholar]
- The MAPK and AMPK signalings: Interplay and implication in targeted cancer therapy. J Hematol Oncol. 2020;13:113.
- [CrossRef] [PubMed] [Google Scholar]
- Melanogenesis and the targeted therapy of melanoma. Biomolecules. 2022;12:1874.
- [CrossRef] [PubMed] [Google Scholar]
- Apigenin: A therapeutic agent for treatment of skin inflammatory diseases and cancer. Int J Mol Sci. 2023;24:1498.
- [CrossRef] [PubMed] [Google Scholar]
- Apigenin as an anticancer agent. Phytother Res. 2020;34:1812-28.
- [CrossRef] [PubMed] [Google Scholar]
- Significance of melanin distribution in the epidermis for the protective effect against UV light. Sci Rep. 2024;14:3488.
- [CrossRef] [PubMed] [Google Scholar]
- Evaluation of antityrosinase activity and mechanism, antioxidation, and UV filter properties of theaflavin. Biotechnol Appl Biochem. 2022;69:951-62.
- [CrossRef] [PubMed] [Google Scholar]
- Beta human papillomavirus 8 E6 induces micronucleus formation and promotes chromothripsis. J Virol. 2022;96:e01015-22.
- [CrossRef] [PubMed] [Google Scholar]
- The role of beta HPV types and HPV-Associated inflammatory processes in cutaneous squamous cell carcinoma. J Immunol Res. 2020;2020:5701639.
- [CrossRef] [PubMed] [Google Scholar]
- Crosstalk between environmental inflammatory stimuli and non-coding RNA in cancer occurrence and development. Cancers (Basel). 2021;13:4436.
- [CrossRef] [PubMed] [Google Scholar]
- The high-risk HPV oncogene E7 upregulates miR-182 expression through the TGF-ß/Smad pathway in cervical cancer. Cancer Lett. 2019;460:75-85.
- [CrossRef] [PubMed] [Google Scholar]
- Anti-aging formula protects skin from oxidative stress-induced senescence through the inhibition of CXCR2 expression. J Ethnopharmacol. 2024;318:116996.
- [CrossRef] [PubMed] [Google Scholar]
- Lipids in ultraviolet radiation-induced immune modulation. Photochem Photobiol Sci. 2020;19:870-8.
- [CrossRef] [PubMed] [Google Scholar]
- Furocoumarins potentiate UVA-induced DNA damage in skin melanocytes. Biochem Biophys Res Commun. 2023;684:149066.
- [CrossRef] [PubMed] [Google Scholar]
- Nucleotide excision repair genes shaping embryonic development. Open Biol. 2019;9:190166.
- [CrossRef] [PubMed] [Google Scholar]
- Going, Toll-like receptors in skin inflammation and inflammatory diseases. EXCLI J. 2021;20:52-79.
- [Google Scholar]
- The critical role of Toll-like receptor-mediated signaling in cancer immunotherapy. Med Drug Discov. 2022;14:100122.
- [CrossRef] [Google Scholar]
- Nutraceutical strategies for alleviation of UVB phototoxicity. Exp Dermatol. 2023;32:722-30.
- [CrossRef] [PubMed] [Google Scholar]
- Autophagy and its relationship to epithelial to mesenchymal transition: When autophagy inhibition for cancer therapy turns counterproductive. Biology. 2019;8:71.
- [CrossRef] [PubMed] [Google Scholar]
- Inactivation of autophagy in keratinocytes reduces tumor growth in mouse models of epithelial skin cancer. Cells. 2022;11:3691.
- [CrossRef] [PubMed] [Google Scholar]
- Oxidative stress and photodynamic therapy of skin cancers: Mechanisms, challenges and promising developments. Antioxidants (Basel). 2020;9:448.
- [CrossRef] [PubMed] [Google Scholar]
- Self-assembling peptides-based nano-cargos for targeted chemotherapy and immunotherapy of tumors: Recent developments, challenges, and future perspectives. Drug Deli. 2022;29:1184-200.
- [CrossRef] [PubMed] [Google Scholar]
- Mast cells as a target-a comprehensive review of recent therapeutic approaches. Cells. 2023;12:1187.
- [CrossRef] [PubMed] [Google Scholar]
- TGFß signaling in photoaging and UV-induced skin cancer. J Invest Dermatol. 2021;141:1104-10.
- [CrossRef] [PubMed] [Google Scholar]
- Combination strategies to augment immune check point inhibitors efficacy-implications for translational research. Front Oncol. 2021;11:559161.
- [CrossRef] [PubMed] [Google Scholar]
- Combination strategies with PD-1/PD-L1 blockade: Current advances and future directions. Mol Cancer. 2022;21:28.
- [CrossRef] [PubMed] [Google Scholar]
- Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs. Cell Death Differ. 2023;30:906-21.
- [CrossRef] [PubMed] [Google Scholar]
- Targeting galectin-driven regulatory circuits in cancer and fibrosis. Nat Rev Drug Discov. 2023;22:295-316.
- [CrossRef] [PubMed] [Google Scholar]
- Actinic keratoses: Review of clinical, dermoscopic, and therapeutic aspects. An Bras Dermatol. 2020;94:637-57.
- [CrossRef] [PubMed] [Google Scholar]