Topical 5-fluorouracil (5-FU) has been described as a treatment for malignant and non-malignant skin conditions [44,45]. Acting as an agent, 5-FU enters cells using the same mechanism as uracil. The metabolism of 5-fluorouracil (5-FU) or its derivatives disrupts intracellular nucleotide pools. This disruption leads to the incorporation of false bases, specifically 5-FU, an analog of uracil, into the DNA. Consequently, this alteration interferes with the processing and functioning of RNA, ultimately resulting in DNA damage. The cytotoxic effects of 5-FU manifest primarily in rapidly proliferating cells within abnormal skin [46,47]. Following the topical application of 5-FU, there is typically a progression of inflammation, erosion, and disappearance of the abnormal lesions. The selective cytotoxicity of 5-FU, with minimal impact on normal skin cells, positions it as a promising therapeutic option in dermato-oncology [47].

Photodynamic therapy (PDT) is a rapidly advancing non-invasive treatment with notable advantages over alternatives [48]. It uses a tumor-targeting photosensitizer, potentially requiring metabolic synthesis, activated by specific-wavelength light. The mechanisms of PDT involve the generation of singlet oxygen (¹O₂) through photosensitizer excitation, inducing necrotic, autophagic, or apoptotic tumor cell destruction [49,50]. PDT is recognized for its therapeutic effectiveness in treating certain types of cancers, including non-melanoma skin cancers. Successful in treating BCC, Bowen’s disease, and AK, PDT offers advantages such as reduced pain and improved patient tolerance, achieving excellent cosmesis. Variable outcomes are observed for nodular BCC, with enhanced outcomes after pre-treatment and repeated PDT cycles. Aggressive BCC subtypes and invasive SCC are less suitable for PDT. Emerging developments involve preventing “field cancerization”, which refers to molecular changes stemming from p53 tumor suppressor gene mutations and leading to subclinical malignant potential after conventional treatment [51]. The significance of cancer-associated fibroblasts and macrophages in resistance to PDT for NMSCs is increasingly acknowledged [52,53].

Laser therapy is a treatment that involves applying a focused light source of a specific wavelength to the tumor. Lasers can be used to cut, burn, or destroy tissues, which can be applied to NMSCs [42]. The treatment of skin cancer involves the use of four main types of lasers: solid-state, diode, dye, and gas lasers [54]. There are two laser treatments used especially for BCC: carbon dioxide laser and pulsed contrast laser. The main benefits of these procedures are satisfactory cosmetic results as well as high cure rates; however, histological evaluations cannot be conducted afterward. In the case of laser therapy for SCC, the literature is far more limited. Initial findings have shown encouraging outcomes in the treatment of SCCs in situ. However, the effectiveness of these treatments in managing invasive SCC has not been conclusively proven [55].

Cryosurgery involves the delivery of liquid nitrogen to freeze the target tumor tissue rapidly and then thaw slowly, leading to local cellular destruction. Regarding NMSC, cryosurgery may be considered in low-risk BCC and should be avoided in SCC due to possible metastasis [56]. Numerous studies have confirmed the high efficacy of cryosurgery in the treatment of BCC, with a 5-year recurrence-free rate of 95–99% [57,58,59]. There are several benefits of cryosurgery. Of those, cryosurgery is quick, cost-effective, and requires no anesthesia. Some potential adverse effects should also be acknowledged, e.g., post-treatment prolonged edema, neuropathic pain, scarring, and hypopigmentation [60].

Aberrantly activated hedgehog signaling plays a pivotal role in developing cancers, including basal cell carcinoma (BCC). Patched homolog 1 (PTCH1) regulates the hedgehog pathway by binding to the smoothened (SMO) protein, an activator of this pathway. Over 90% of all BCC cases exhibit deletion mutations in the PTCH1 gene or activating mutations in the SMO gene, leading to enhanced hedgehog pathway activity and the development of BCC. In recent years, inhibitors have been developed to attenuate hedgehog signaling. Two of them, vismodegib and sonidegib, have been approved for use in advanced and metastatic BCCs. Other molecules are currently under investigation in clinical trials [61,62,63,64].

Immunotherapy is playing an increasingly crucial role in the treatment of advanced cancers. In the case of skin cancers, it is employed in locally advanced and unresectable cSCCs (cutaneous Squamous Cell Carcinomas), as well as, more recently, in BCCs resistant to hedgehog inhibitors. In NMSC immunotherapy, checkpoint inhibitors are used to assist the host immune system in more effectively combatting cancer cells by modulating the immune response and enhancing the activity of cytotoxic T cells [65,66]. Effective targets for checkpoint inhibitors in NMSC include the PD-1/PD-L1 pathway (pembrolizumab, cemiplimab, and avelumab) and CTLA-4 (ipilimumab) [37]. The use of neoadjuvant immunotherapy can allow for the surgical treatment of previously unresectable diseases and potentially improve the quality of life for individuals with locally advanced diseases [67]. Despite satisfactory responses to immunotherapy in NMSCs, the associated immune-related adverse events require monitoring. Consequently, clinical research efforts should focus on discovering a novel treatment that enhances tumor response while minimizing toxicity [37].

Curcumin, a vibrant yellow plant polyphenol, has played a multifaceted role throughout history, serving as both a cherished spice and a valuable medicinal agent. It is a major part (74.9%) of a spice, curcuminoid, which likewise consists of desmethoxycurcumin (DMC) (20.1%) and bisdemethoxycurcumin (BDMC) (4.9%) [72]. Derived primarily from Curcuma longa, more commonly known as turmeric, curcuminoids are meticulously isolated from the rhizomes of this plant [73]. Curcumin’s rich history encompasses diverse applications, ranging from its traditional use as an herbal supplement to its incorporation into food coloring and preservation, flavoring, and cosmetics [74].

Notwithstanding its lack of official approval for therapeutic use, curcumin has demonstrated efficacy against diverse diseases, including breast, ovarian, and prostate cancer, human immunodeficiency virus, epilepsy, psoriasis, and diabetes. Notably, curcumin exhibits a favorable safety profile even at gram doses, without side effects up to 8000 mg per day [75,76,77,78]. Researchers have explored the potential application of curcumin as a pharmaceutical agent to manage and treat cancer-related symptoms, such as pain, fatigue, depression, and neurodegeneration, yielding promising results [79]. Curcumin exerts its impact on cancer progression through the selective modulation of various signaling pathways [80].

In terms of UVB exposure causing damage both in vitro and in animals, topical application of curcumin significantly mitigates acute UVB-induced damage by reducing the release of lactate dehydrogenase, intracellular ROS, and DNA damage [81]. An animal study showed that both superficial and oral applications of curcumin before chronic UV exposure delayed tumor onset [82].

UVB exposure triggers mTOR and fibroblast growth factor receptors (FGFR) signaling pathways that play a pivotal role in skin tumorigenesis, including SCC, BCC, and AK. Notably, the pre-treatment application of the C3 curcuminoid complex hinders UVB-induced fibroblast growth factor-2 (FGF-2) expression, FGF-2-mediated cell proliferation, progression, and colony formation, along with suppressing mechanistic target of rapamycin (mTOR) pathway (mTORC1/mTORC2 network) as well as FGFR2 phosphorylation in JB6 epithelial cells sensitive to promotion. Oral application of the C3 complex on mice significantly inhibits UVB-induced epidermal hyperplasia and hyperproliferation likewise [83].

The predominant body of research on curcumin with respect to non-melanoma primarily focuses on SCC, particularly within the domain of head and neck SCC (HNSCC) [84]. The investigation into the involvement of curcumin in HNSCC was carried out through a clinical trial. It demonstrated that the administration of microgranular curcumin might be linked to a notable reduction in FGF-2, macrophage colony-stimulating factor, and interleukin-17 involved in the modulation of angiogenesis and cellular invasion of HNSCC. These findings suggest that curcumin could serve as a prospective angiogenic inhibitor in HNSCC, potentially impeding the advancement of pre-neoplastic lesions into invasive cancer [85].

Curcumin’s hydrophobic nature and low solubility limit its oral bioavailability, posing challenges for therapeutic use. Topical treatment protocols may mitigate these challenges and offer clinical advantages. Current research has explored nanoformulations, such as diverse types of liposomes or PEGylated solid lipid nanoparticles, to enhance solubility and address these issues [86]. The topical application of a curcumin-loaded liposome-siRNA complex induced a more pronounced inhibition of SCC cell model growth and apoptosis events compared with the control group [87]. Moreover, the curcumin-loaded nanopatterned films presented good cytotoxicity against the same SCC cell model [88]. However, topical curcumin treatment may be restricted by the potential for contact dermatitis, a phenomenon observed in humans [89]. The clinical trial mentioned above presented a resolution to the challenges associated with the oral administration of curcumin. The oral transmucosal delivery of microgranular curcumin has demonstrated heightened curcumin bioavailability, aligning with significant biological effects that have the potential to impede the progression of pre-neoplastic lesions to invasive SCC [85]. Notably, piperine, a natural anti-cancer agent, enhances curcumin bioavailability by 2000% by inhibiting glucuronidation [90]. Nevertheless, ongoing advances in the curcumin formulation may further optimize its responses and efficacy.

Gallic acid (GA) is a naturally occurring compound found in various plants, including gallnuts, sumac, witch hazel, tea leaves, oak bark, and others. It is known for its potent antioxidant properties. GA is often used in the pharmaceutical and food industries due to its health benefits and as a component in some inks and dyes. It has been studied for its potential therapeutic effects, including an anti-cancer effect [91].

GA acts against BCC by targeting and inhibiting HSP90AB1, a protein associated with cancer aggressiveness. GA reduces the migration and proliferation of BCC cells without increasing Reactive Oxygen Species (ROS) levels or causing death in keratinocytes (healthy skin cells). This suggests that GA can effectively target and impair BCC cells while preserving healthy cells, making it a potential therapeutic agent for treating BCC [92].

GA impacts SCC by inhibiting HSP90AB1, a protein associated with cancer’s invasiveness and aggressiveness. GA effectively reduces cell migration and proliferation in SCC, promoting cell death and significantly lowering HSP90AB1 levels in SCC cells [92]. This action of GA highlights its potential as a therapeutic agent in treating SCC by targeting specific cancer-related proteins and pathways.

Silymarin is derived from the seeds of milk thistle (Silybum marianum), which is an annual Mediterranean native herb [93]. This extract is a flavonolignan complex and contains other polyphenolic compounds, amongst which silibinin can be found as the major one [94]. This compound has built itself a positive reputation for several centuries due to its hepatoprotective effects regarding its antioxidant and anti-inflammatory activities [95]. Lately, silymarin has also been used in dermatology and cosmetology due to its protective and preventive potential against UVB-induced NMSC in pre-clinical skin cancer studies [96]. Over the last two decades, many studies have shown its anti-cancer activity, amongst which research conducted by Agarwal and colleagues on 7, 12-Dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis model indicated it. By inhibiting the activity of epidermal ornithine decarboxylase, silymarin suppressed the skin cancer progression [96]. Moreover, silibinin has been proven in vitro in animal models to act against UVB-induced thymine dimer formation, inhibiting carcinogenesis by increasing p53 levels. It also promotes DNA repair and induces anti-inflammatory responses, as well as targeting aberrant signaling pathways. Silibinin could be proven to have a successful therapeutic effect against skin SCC and BCC in humans as it targets inflammatory and oxidative stress signaling [96].

Resveratrol is a naturally occurring polyphenol found in various plants, including grapes, berries, and peanuts. It is particularly noted for its presence in red wine. It has the potential to positively impact both the prevention and management of inflammatory disorders and cancer as well as slowing the aging process [97,98,99]. It is comprised of a pair of phenolic rings connected by a double styrene bond, creating the structure known as 3,5,4′-Trihydroxystilbene [100]. Earlier research illustrated that resveratrol has pleiotropic effects instead of depending on a single mode of action. It has been shown that resveratrol inhibits proliferation by downregulating NFkB, inhibits epithelial-mesenchymal transition dependent on TGF β/Smad, decreases the β-catenin-dependent pathway to impede invasion and migration, and influences angiogenesis by inhibiting HIF-1 and expediting its ubiquitination [101,102,103,104]. Moreover, an oral squamous cell carcinoma cell lines study showed that resveratrol induces apoptosis and G2/M phase cell cycle arrest [105]. However, determining the optimal dosage of resveratrol for maximizing its health benefits while mitigating the risk of toxicity represents a significant and ongoing area of scientific inquiry [106]. Nonetheless, resveratrol’s capacity to target various aspects of tumor development has enhanced its value as a supplementary agent in combination with other treatments, enhancing its efficacy through synergy (Figure 2) [98].

Quercetin (3,5,7,3′,4′-pentahydroxyflavone) shows a wide range of potential activities, including anti-cancer, anti-diabetic, anti-inflammatory, antioxidant, anti-microbial, anti-arthritic, cardioprotective, and wound-healing effects [113]. Quercetin is found in onions, grapes, berries, cherries, broccoli, and citrus fruits [114]. An in vitro study by Stevanto et al. showed a mathematically calculated Sun Protection Factor (SPF) of selected natural compounds. Despite displaying relatively low UVB protection (SPF~10) compared with apigenin (SPF = 28.8) and kaempferol (SPF = 24.9), quercetin was characterized by absorption at relatively high absorption levels (360–375 nm) compared with other flavonoids. Furthermore, quercetin showed the highest UVA protection among flavonoids, measured by the UVA/UVB ratio parameter [115].

However, quercetin is characterized by rapid metabolism and excretion, low stability, poor water solubility, and poor absorption. Thus, there is a need to elaborate an effective drug-delivery system for topical application. Nan et al. found that encasing quercetin in chitosan nanoparticles provided enhanced stability and minimal cytotoxicity while being readily absorbed by HaCaT cells and capable of passing through the epidermis layer. The authors found that quercetin blocked the NF-Κβ/COX-2 signaling pathway [116]. In another study conducted in vivo on male Wistar rats and in vitro on skin cancer A431 cell lines, Chitkara et al. presented quercetin nanoemulgel prepared using the ultrasonication emulsification method. The nanoemulgel effectively mitigated the skin edema from UVB radiation and showed neither skin irritation nor organ toxicity in male Wistar rats [117].

Kaempferol (5,7,4′-trihydroxyflavone) is rich in tea, broccoli, cabbage, kale, beans, endives, leek, tomatoes, strawberries, and grapes. Its pharmacological activities include antioxidant, anti-inflammatory, anti-microbial, anti-cancer, cardioprotective, neuroprotective, anti-diabetic, anti-osteoporotic, anxiolytic, analgesic, and anti-allergic activities [118].

Similar to quercetin, kaempferol exhibits absorption at relatively high absorption levels (360–375 nm) compared with other flavonoids. Moreover, kaempferol retains moderate UVB protection (SPF = 24.9) [115]. Yao et al. demonstrated chemopreventive properties against UV-induced carcinogenesis in a mouse model. Mice with topically administrated kaempferol presented remarkably delayed tumor growth. The authors highlighted that the inhibitory effects of kaempferol are caused by targeting RSK2 and MSK1 [119].

Epigallocatechin gallate (EGCG), found primarily in green tea, has been widely reported to display antioxidative, anti-inflammatory, anti-cancer, anti-proliferative, and chemopreventive activities [120].

A study on A431 and SCC13 human skin cancer cell lines revealed that ECGC exhibits anti-proliferation potential by inactivating β-catenin signaling. Downstream targets of β-catenin signaling, including MMPs, c-Myc, and VEGF, were also suppressed. Concomitantly, EGCG decreased the levels of COX-2 and PGE2. [121]. Moreover, a study on human skin fibroblasts (HSF) demonstrated that ECGC delayed UVA-induced photoaging [122].

Nevertheless, EGCG is unstable under ambient conditions, while its epimer, gallocatechin gallate (GCG), is chemically more stable. Sheng et al. showed that GCG may protect against UVB-induced skin damage by increasing skin elasticity and the number of collagen fibers in a study on a mouse model mouse model. Based on the findings from transmission electron microscopy (TEM), the authors suggested that GCG alleviates UVB-induced aberrations in mitochondria and the formation of melanosomes [123].

Apigenin (4′,5,7-trihydroxyflavone) is a compound of parsley, chamomile, celery, vine spinach, artichokes, and oregano investigated on anti-cancer mechanisms in SCC cell lines [124]. Wang et al. showed that apigenin might induce apoptosis by downregulating sulfiredoxin expression and activating the MAPK signaling pathway [125]. In another in vitro SCC model, apigenin administration resulted in a decrease in microtubule-associated protein 1 light chain 3 (LC3) turnover and green fluorescent protein (GFP-LC3), suggesting autophagy inhibition [126]. Stevanto et al. showed that apigenin has the greatest potential in UVB protection among flavonoids (SPF = 28.8) [115]. Furthermore, apigenin was found to suppress the expression of IKKα in mouse cell lines. As a result, epithelial-mesenchymal transition (EMT) was diminished, indicating potential anti-metastatic activity [127]. Apigenin has also been found to reduce the synthesis of COX-2, PGE2, EP1, and EP2 in mouse models [128].

Daidzein, genistein, biochanin A, glycitein, and formononetin are phytoestrogen isoflavolones. Phytoestrogens are compounds derived from plants that are structurally similar to 17β-estradiol. [129,130]. Consequently, phytoestrogens may act through estrogen receptors to increase the production of collagen, hyaluronic acid, and extracellular protein matrix. Furthermore, phytoestrogens contribute to increased skin vascularization, cell proliferation, and protection against oxidative stress [131].

Daidzein (4′,7-dihydroxyisoflavone) is a phytoestrogen isoflavone derived from leguminous plants, particularly soybeans. 7,3′,4′-trihydroxyisoflavone (734-THIF), a secondary metabolite of daidzein, has been found to have antioxidant, atopic dermatitis-relieving, melanin inhibiting, and skin cancer chemopreventive activities [132,133,134]. Similar to quercetin, due to its poor water solubility and poor absorption, its topical administration is limited. Thus, Huang et al. proposed E100 (EE)–polyvinyl alcohol (PVA)-loaded 734-THIF nanoparticles that present improved water solubility and enhanced skin penetration on HaCaT cell lines [132]. In another study, polyvinylpyrrolidone K30-based 734-THIF nanoparticle powder also showed increased physiochemical properties. Additionally, 734-THIF reduced the overexpression of COX-2 and MMP-9 by downregulating MAPK pathway signaling in particulate matter-exposed HaCaT keratinocytes [135]. That suggests potential anti-inflammatory, anti-pollutant, and anti-aging properties of 734-THIF.

Studies in vitro, in vivo, and animal models have shown that genistein (4′,5,7-trihydroxyisoflavone), a soybean derivative, is another candidate to protect against UVB-induced inflammation and aging. Tang et al. found in vivo that genistein suppresses inflammatory cytokines, notably CXCL1, IL-1, MIF, and PLANH1. In animal models (dorsal skin of rats), topical-administrated genistein decreased the number of skin folds and wrinkles induced by UVB. Furthermore, a diet reach in genistein in human participants significantly reduced the severity of UVB-induced wrinkling [136].

Another study in an animal model by Terra et al. showed a mechanism potentially linking genistein to photoprotection. NO (nitric oxide) is a factor that contributes to the inhibition of cell proliferation after UVB exposure. The authors found that genistein has antioxidant activity preventing the reaction of H₂O₂ with NO, consequently reducing ONOO- formation. This promotes cell proliferation and tissue protection [137].

Biochanin A (5,7-dihydroxy-4’-methoxyisoflavone) is found in red clover, chickpeas, soybeans, and other herbs [138,139]. Lim et al. observed that biochanin A inhibits the UV-induced expression of COX2 via MLK3 inhibition in vitro [140]. Since COX2 may inhibit the proliferation of SCC cells in vivo, biochanin A is a promising putative anti-cancer compound [140].

Vitamin A forms a wide group of substances, such as retinoids, retinol, retinyl palmitate, and beta-carotene, which can be derived from animal sources, such as eggs, milk, organ meats, cheese, or fish [141,145]. Of the substances mentioned above, retinoids are particularly potent in the treatment and prevention of non-melanoma skin cancer and have the ability to inhibit the development of skin carcinogenesis. They are vital for processes of cell turnover, immunity, proliferation, barrier functions, angiogenesis, and differentiation, playing a key role in the normal functioning and abnormalities of the skin. Moreover, through the thickening of the epidermis, they lower the amount of UV radiation that reaches the strata below [36,42]. However, retinoids contribute to more anti-cancer mechanisms. In terms of restraining cSCC, all-trans-retinoic acid (ATRA) represses the overexpressed in some aggressive cancers’ activator protein-1 and diminishes activation of STAT3 in keratinocytes, whereas STAT3 encourages keratinocyte proliferation, which potentially leads to its later malignancy. What is more, as retinoids play a role in angiogenesis, which is a vital case in cancer formation, retinoid treatment might efficiently inhibit skin cancer growth by impeding angiogenesis [36]. Moreover, via in vitro and in vivo testing to understand how retinol works, this mechanism of anti-cancer action presented by retinol is considered its primary [145]. Retinoids have shown effectiveness in treating certain types of skin cancers, such as BCC or cSCC. They have been proven beneficial in both prevention and therapy for certain types of skin cancers, with specific applications approved by the FDA and off-label uses [36].

Vitamin C is an intracellular antioxidant that can be found in fruits and vegetables. In the available studies, it has been shown to provide protection against UV radiation and carcinogenesis. Moreover, scientists providing an investigation on cultured keratinocytes discovered that the combination of vitamins C and E had a beneficial effect. They observed that these vitamins were able to counteract the rise in ROS caused by UVB irradiation. Moreover, the combination of vitamins C and E provided protection against apoptosis triggered by UVB exposure. This suggests that the antioxidant properties of vitamins C and E may play a role in mitigating the harmful effects of UVB radiation on skin cells. However, it is important to note that further investigation is necessary to comprehend the mechanisms and practical implications of these findings fully. Vitamin C has also been found to have an impact on DNA repair. In a study involving human dermal fibroblasts treated with vitamin C, researchers observed an upregulation of genes related to DNA replication and repair. Additionally, the fibroblasts exhibited a faster repair process for DNA bases that had been damaged by oxidative stress. Vitamin C has been found to produce hydrogen peroxide in extracellular fluid, and this is believed to contribute to its anti-cancer properties through a process called the Fenton reaction. A recent study by Ngo et al. explored the pre-clinical evidence of how high doses of ascorbate can affect redox imbalance, epigenetic re-programming, and oxygen-sensing regulation, all potential mechanisms of its anti-cancer action. Interestingly, the metabolic effects of ascorbate have minimal impact on normal cells [146].

Vitamin E, a lipid-soluble antioxidant, represents eight corresponding substances—four tocotrienols and four tocopherols. Its main sources are nuts, plant-based oils, soybeans, and wheat germ [146]. Vitamin E has been demonstrated to prevent the peroxidation of membrane lipids caused by ROS. In a study involving mouse keratinocytes, it was found that pre-treatment with vitamin E prior to UVB radiation resulted in a reduction in UVB-induced damage to the epidermis [146,147]. Similarly, in human fibroblasts exposed to UVA light, both vitamins C and E exhibited the potential to provide protection against the harmful effects of UVA radiation [146,148]. Included in the vitamin E group is tocopherol, which has been found to inhibit the activity of protein kinase C (PKC) and suppress tumor angiogenesis. However, the anti-cancer effect of vitamin E on NMSC has not yet been fully proven [149]. Several studies have indicated that there is no significant association between the serum level or intake of vitamin E and the risk of BCC [149]. Moreover, the randomized double-blinded trial of 7000 adults conducted by Argos et al. did not show any beneficial effect of treatment with vitamin E [150]. No studies have indicated any significant influence of vitamin E on NMSC.

Vitamin D is a hormone that can be obtained from sources such as fish or mushrooms [151]. This compound possesses antioxidant as well as immunomodulatory properties, and its anti-cancer effect on NMSC should be confirmed [151]. What has been found in this field, according to in vitro animal models, is that vitamin D has the ability to modify cancer cell proliferation, cell death, differentiation, and tumor angiogenesis, making it a potential candidate agent for cancer regulation [151,152]. However, the question of whether vitamin D prevents cancer in humans or limits its progression is still unresolved and requires further investigation [142,151]. Various studies have considered vitamin D receptors to be tumor inhibitors in the skin due to their factors that are believed to alter cancerous cell functions [151]. However, studies have also suggested that higher serum levels of vitamin D3 are associated with a linear dose–response relationship. It is important to note that this association may be influenced by the dual effect of UVB radiation. While UVB exposure enables vitamin D synthesis, it can also lead to DNA damage, increasing the risk of skin cancer. Therefore, the relationship between vitamin D levels, UVB exposure, and skin cancer risk is complex and requires further investigation. What is more, another study indicated that suppressing strong carcinogens such as 7,12-dimethylbenzanthracene puts into effect a photoprotective function against UV radiation exposure, protecting against NMSC [42]. That is why vitamin D requires further research on its anti-cancer properties.

Cryptolepine is a type of alkaloid obtained from the roots of a shrub, Cryptolepis sanguinolenta, which is found in Central and West Africa. It has shown numerous pharmacological and biological activities, amongst which anti-inflammatory activity can be highlighted. Through the inhibition of COX-2/PGE signaling, TNFα and iNOS cryptolepine have proven their anti-inflammatory activity in various animal model systems. Cryptolepine’s anti-tumor potential has been tested as the emergence and advancement of cancers are strongly linked to inflammation. The results have proven its cytotoxic potential against cancer, but the mechanism behind it has not been fully recognized. The research has been conducted to detect how criptolepine influences cancer cells using SCC-13 and A431 cell lines as an in vitro model. Treating NMSCC with cryptolepine significantly reduced topoisomerase activity, presumably due to DNA damage, which led NMSCC to decrease cell viability and their ability to form colonies and increase cell death through apoptosis. As topoisomerases are essential for DNA replication as well as cell proliferation, and their activity can be impaired because of cancer cells, it is important to inhibit topoisomerase functions and induce DNA damage, leading to apoptosis [155]. One of criptoleptine’s mechanisms of action that induces DNA impairment is the enhancement of the phosphorylation of ATM/ATR, BRCA1, Chk1/Chk2, and γH2AX. This compound also activated the p53 signaling pathway and downregulated cyclin-dependent kinases, cyclin D1, cyclin A, cyclin E, and proteins involved in cell division. What is more, the integrity of the mitochondrial membrane potential is compromised, and relief of cytochrome c occurs. All these actions end up with anti-proliferative and pro-apoptotic effects [93,155].

The most investigated terpenoid in terms of non-melanoma skin cancer is inegnol mebutate, a diterpene ester isolated from the Euphorbia peplus plant [160]. Its anti-proliferative activity comprises mitochondrial swelling, disruption of membrane potential, and a decline in adenosine triphosphate synthesis that causes necrotic cell death [161]. Furthermore, residual dysplastic epidermal cells may be eliminated through neutrophil-mediated antibody-dependent cytotoxicity [162]. Notably, ingenol mebutate represents the natural compound that has progressed to clinical trials for the treatment of NMSC. In 2013, ingenol mebutate (Picato^®) obtained marketing authorization from the European Medicines Agency (EMA) for the topical treatment of non-hyperkeratotic, non-hypertrophic AK in adults [163]. The EMA mandated a study to investigate the risk of SCC associated with ingenol mebutate. The results of the 3-year safety study revealed a higher incidence of skin cancer, leading the EMA to recommend suspending the license for ingenol mebutate gel in 2020 as a precaution pending further review. The Medicines and Healthcare products Regulatory Agency (MHRA) reported that the final study results among 484 patients indicated a higher occurrence of SCC in those using ingenol mebutate gel compared with imiquimod (3.3% vs. 0.4%) [164,165,166]. Stocks of the gel have been recalled in the UK and Canada, and clinicians have been advised to cease prescribing it and explore alternative treatments for AK [165,167].

The terpenoid being researched in the field of skin cancers is glycyrrhizic acid (GlA). GlA is extracted from Glycyrrhiza glabra and demonstrates significant anti-tumor activity against melanoma by targeting the tumor microenvironment (TME) and modulating immune responses. GlA’s mechanisms include inducing apoptosis in melanoma cells and reducing their proliferation [168]. This is achieved by upregulating pro-apoptotic factors such as Bax and caspase 3 and downregulating the anti-apoptotic factor Bcl2. Altering cytokine profiles within the TME, GlA shifts the balance from anti-inflammatory to pro-inflammatory cytokines, promoting a Th1 immune response conducive to tumor rejection. GlA impacts T Regulatory Cells (Tregs) and Myeloid-Derived Suppressor Cells (MDSCs) by inhibiting STAT3 phosphorylation, a crucial factor in their immunosuppressive function. This leads to reduced Treg markers (Foxp3, GITR, and CTLA4) and the downregulation of MDSC-associated factors (Cox2, PGE2, and Arginase 1) [168]. When combined with Mycobacterium indicus pranii (Mw), an immunomodulator, GlA shows enhanced effectiveness, particularly against advanced-stage melanoma. [168] GlA’s multifaceted approach against melanoma positions it as a potential candidate for melanoma immunotherapy and cancer treatment.

GlA provides protective effects to skin cells against the stresses caused by UVB radiation, which is responsible for most non-melanoma skin cancers. Through various pathways, GlA demonstrates its photoprotective effects against UVB radiation-induced damage in primary human dermal fibroblasts (HDFs). GlA significantly reduces cell death in UVB-irradiated HDFs and prevents UVB-induced Cyclobutane Pyrimidine dimers (CPDs) formation, a major form of DNA damage caused by UVB [169]. It also diminishes DNA fragmentation, suggesting its role in protecting HDFs from UVB-induced DNA damage. GlA exhibits strong antioxidant properties by quenching ROS generated due to UVB exposure [169]. GlA relieves HDFs from the oxidative stress-mediated endoplasmic reticulum (ER) stress [169]. It also influences the process of autophagy—a cellular degradation and recycling process. Moreover, GlA treatment leads to changes in the expression levels of autophagy-related proteins, such as p62, BECN1, mTOR, and ATG7, especially in the initial hours following UVB irradiation [169]. GlA downregulates key DNA damage marker proteins, such as ATM, ATR, Chk1, Chk2, DDB2, P53, and χH2AX, in HDFs irradiated with UVB. Additionally, GlA stabilizes the AKT/PTEN axis, which is known to be affected by UVB irradiation. GlA stabilizes this axis, indicating its role in protecting cells against UVB-induced effects [169]. The use of chloroquine, an autophagy inhibitor, potentiates UVB-induced DNA damage in GlA-treated HDFs, while rapamycin, an autophagy activator, enhances GlA’s protective effect against UVB-induced damage [169].

Betulin and betulinic acid, naturally occurring triterpenes commonly derived from the bark of birch trees, are known for their protective properties against conditions such as oxidative stress, inflammation, and cancer [93,170]. Betulin is classified as a lupine-type compound and is distinguished by the presence of an isopropylidene group and a five-membered ring [171]. These compounds promote the differentiation of normal human keratinocytes and induce cytotoxic, anti-proliferative, and apoptotic responses in tumor cells through the direct interaction with mitochondria by rendering the mitochondrial membrane permeable, leading to the release of apoptogenic proteins into the intermembrane space. Interestingly, this apoptotic process is triggered independently of the p53 gene and excludes the CD95 receptor. Additionally, it modulates the action of the NFkB transcription factor and activates the Nrf2 pathway [172,173,174].

In the context of NMSC, the anti-cancer properties of betulinic acid, betulin, and its new esters containing lysine or ornithine side chains were investigated in an in vitro study. It was indicated that newly modified compounds originating from betulin hold significant therapeutic potential for actinic keratosis, and the most significant benefit is that they are safe for normal human keratinocytes [175]. Betulin has also been confirmed as a potent anti-mutagenic agent against skin carcinogenesis in in vivo research. In experiments using chemically damaged mice skin, a topical formulation with betulin nanoemulsion was tested. The skin damage could lead to significant pathologies, including neoplasms. Betulin reduced skin lesions and irritation, notably decreasing erythema, and exhibited inhibitory effects on the initiation and promotion of skin tumors. Additionally, betulin increased the respiratory function of isolated liver mitochondria in a two-stage model of skin carcinoma in mice. It also showed the potential to reduce damage in vital organs, such as the liver, due to the slow penetration of carcinogens applied to the skin surface, resulting in toxic effects by carcinogen penetration [176].

Sulforaphane (SFN), a constituent of the isothiocyanate family, is notably present in significant amounts in both broccoli and its sprouts. This family encompasses sulfur-containing compounds, including allyl, benzyl, phenylethyl, isopropyl, and methyl thiocyanate. These compounds are widely distributed among cruciferous vegetables, such as cauliflower, kale, watercress, and cabbage [182,183]. Research indicates that SFN demonstrates efficacy in the prevention or reversal of various neoplasms, including breast, colon, prostate, and lung cancer and melanoma [184,185,186,187].

SFN exhibits differential effects on both normal and cancer cells. In the latter, SFN induces cell cycle regulatory proteins such as p21 and p16, leading to apoptosis and inhibition of cell proliferation [188]. This upregulation is also attributed to the inhibition of histone deacetylase (HDAC) expression and its activity in cancer cells. The combination of green tea polyphenols (GTP), a dietary DNMT inhibitor, with SFN was shown to reactivate p21 and Klotho genes through histone acetylation [189]. On the contrary, normal keratinocytes show resistance to the SFN-induced inhibition of HDAC and cell proliferation compared with cancer cells [21].

SFN exhibits potent anti-cancer effects, including against skin cancer, by inhibiting HDACs and DNA methylation [190]. SFN reactivates Nrf2, a transcription factor for antioxidant enzymes, by down-regulating DNA methyltransferases (DNMTs) and HDACs in JB6 mouse skin epidermal cells exposed to TPA, thus suppressing TPA-induced malignant transformation [191]. Through the involvement of the Nrf2-dependent mechanism, the topical application of SFN in mouse skin results in increased glutathione (GSH) and glutathione S-transferase 4 (GST4) syntheses, which inhibit skin mutagenesis [192].

Another anti-tumor mechanism of SFN relating to epigenetic regulators includes polycomb group proteins (PcG), which are implicated in chromatin remodeling and the inhibition of gene expression. Elevated expression of PcG proteins, such as Bmi-1, Ezh2, and SUZ12, is observed in various skin cancers [190]. High Bmi-1 expression promotes transcriptional inactivation of regulatory cell cycle proteins, such as ARF and INK4A, by recruiting histone methylation complexes (PRC2 and PRC1). Treatment with SFN inhibits cell proliferation by reducing the expression of Bmi-1 and Ezh2.

Among non-melanoma skin cancers, SCC has been the most frequently investigated in the context of SFN treatment. In SCC, exposure to SFN hinders cancer progression and in vivo metastasis by diminishing arginine methylation at histone 3 (H3). This reduction involves SFN-induced proteasomal degradation of arginine N-methyltransferase 5 (PRMT5) and methylosome protein 50 (MEP50). Both enzymes are responsible for arginine methylation at H3 and H4, respectively, leading to decreased levels of dimethylated arginine 3 at H4 (H4R3me2) [193]. Moreover, using a biotin-tagged SFN analog (Biotin-ITC) and kinetic analysis, it was shown that SFN covalently binds to recombinant type 2 transglutaminase (TG2), irreversibly inhibiting its transamidase activity. This induces an open/extended conformation and partially inhibits GTP binding, which is crucial for maintaining the aggressive SCC phenotype (Figure 8) [194]. Furthermore, the combined therapy of SFN and cisplatin for SCC suppressed tumor formation and reduced the population of cancer stem cells within the tumor [195].

Lycopene, an antioxidant derived from plants such as tomatoes, watermelons, red carrots, and papayas, exhibits potential bioactivity and notable health benefits. This compound comprises eight isoprene units linked together, forming a tetraterpene structure. Additionally, it contains a total of 11 linear double bonds. Research has focused on its anti-cancer properties, including inhibiting apoptosis and cell proliferation and affecting various signal transduction pathways. Several studies highlighted its biological activity concerning skin cancers and photoprotection [205,206]. It has been shown that regular consumption of lycopene can protect the human skin from the effects of UVR, including erythema, alterations in the extracellular matrix, and damage to mitochondrial DNA [207].

In chemically induced cutaneous tumor mice and cell models, lycopene reduced both the incidence and multiplicity of cutaneous tumors and inhibited the tumorigenesis of normal cutaneous cells during the promotion phase. This effect was associated with activating antioxidant enzymes and the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). Additionally, lycopene increased the expression of the autophagy protein p62, leading to the degradation of Keap1 (Kelch ECH associating protein 1), the main protein responsible for keeping Nrf2 in the cytoplasm [208].

Astaxanthin (ASX) and fucoxanthin (FX) are unique marine carotenoids known for their remarkable antioxidant qualities. Astaxanthin is composed of a polyene chain connecting two terminal β-ionone-type rings. The molecule features two asymmetric carbons situated at the 3,3′-position of the β-ionone ring, and each end of the molecule is equipped with a hydroxyl group. Additionally, oxygen is incorporated into the ring system in the form of hydroxyl and keto groups [209]. Fucoxanthin possesses a distinctive structure, featuring an uncommon allenic bond, nine conjugated double bonds, a 5,6-monoepoxide, and several oxygenic functional groups, such as hydroxyl, epoxy, carbonyl, and carboxyl moieties [210]. These carotenoids have demonstrated exceptional effectiveness in mitigating various types of photodamage. This is attributed to its antioxidant capabilities and the initiation of alternative pathways. [211,212]. Research suggests the potential health-promoting effects of ASX and FX in the prevention of skin cancer.

It has been indicated that FX and AX play a role in activating the Nrf2 signaling pathway, prompting the epigenetic demethylation of CpG sites within Nrf2 and demonstrating the ability to inhibit the TPA-induced transformation of mouse skin JB6 P+ cells [213]. Moreover, it has also been shown that in human keratinocytes, FX treatment augments cellular antioxidant defense by inducing Nrf2-driven expression of enzymes involved in GSH synthesis via PI3K/Akt signaling [214].

It has been shown that prior exposure to 5 µM of ASX in human keratinocytes (HaCaT) 24 h before UVB exposure or the topical application of a 0.02% ASX gel following chronic UVB irradiation in male Wistar mice (administered three times per week for 4 weeks), demonstrated the ability to hinder oxidative DNA damage [215,216]. Rao et al. investigated astaxanthin mono- (AXME) and diesters (AXDE) for anti-cancer potency in rat cancer models. AXDE and AXME exhibited a significant reduction in UV-7,12-dimethylbenz(a)anthracene (DMBA)-induced tumor incidences, reaching 96% and 88%, respectively. This effectiveness was notably higher compared with the reduction achieved with ASX alone, which was at 66%. It has been suggested that this is due to the better bioavailability of ester compounds [217].