Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Skin cancer is a global threat to the healthcare system and is estimated to incline tremendously in the next 20 years, if not diagnosed at an early stage. Even though it is curable at an early stage, novel drug identification, clinical success, and drug resistance is another major challenge. To bridge the gap and bring effective treatment, it is important to understand the etiology of skin carcinoma, the mechanism of cell proliferation, factors affecting cell growth, and the mechanism of drug resistance. The current article focusses on understanding the structural diversity of skin cancers, treatments available till date including phytocompounds, chemotherapy, radiotherapy, photothermal therapy, surgery, combination therapy, molecular targets associated with cancer growth and metastasis, and special emphasis on nanotechnology-based approaches for downregulating the deleterious disease. A detailed analysis with respect to types of nanoparticles and their scope in overcoming multidrug resistance as well as associated clinical trials has been discussed.
Keywords: Skin cancer, Melanoma, Non-melanoma, Etiology, Phytocompounds, Toxicity, Targeted therapy, Combination therapy, Nanotechnology
Skin cancer (SC), is one of the most devastating cancers of the present decade, and the fifth commonest form of cancer [1–3]. It is further predicted to surpass heart disease as the main cause of mortality and the biggest obstacle to extending life expectancy in the next decades. According to the annual status report from the International Agency for Research on Cancer, there were approximately 9.6 million cancer-related fatalities and 18.1 million new instances of cancer globally in 2018. As per the statistics presented by the American Cancer Society, the new cases of melanoma among all cancers are estimated to be 6% in males and 4% in females in the year 2023. Furthermore, it is expected that the number of new cases would continue to rise over the next 20 years [4–8].
The etiology primarily lies beside the abnormal skin cell proliferation facilitated by the unrepaired DNA of skin cells which owes to DNA mutations or genetic defects. The skin's tissue is divided into two layers: the top epidermis, which is made up of epithelial cells and pigmented melanocytes, and the bottom dermis, which comprises a layer of connective tissue that holds blood vessels, hair follicles, and sweat glands [9–13]. Cancer cells that emerge from mutations in skin melanocytes are termed malignant melanoma. Non-melanoma skin cancer (NMSC), which develops from the epidermis, is the kind of skin cancer that is most often seen worldwide. Based on the kind of cells involved, it is further classified as Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In around 25% of the cases that were recorded, a mole transformed into a case of Multiple Myeloma (MM) grew and metastasize. A significant risk of recurrence is associated with this MM kind of skin cancer. NMSC rarely migrates into the deeper tissues of the epidermis if unnoticed. It can only be easily eliminated when it is found at an early stage. Thus, SC must get significant funding for technology and treatment since it negatively affects the social and psychological well-being of an individual [14–17].
Till date, the treatment includes surgery, chemotherapy, and radiation therapy. However, such treatments do not cure ailments, are painful for the patients, and have several negative consequences. They often affect normal, healthy cells as well without causing sufficient toxicity to the cancer cells [3, 18–21]. Since there are tumor-ablative and function-reserving oncologic treatments, the use of phototherapies, such as photodynamic therapy (PDT) and photothermal therapy (PTT), in clinical cancer therapy offers great potential. Safe phototherapeutic compounds may be triggered by light irradiation throughout phototherapies, selectively eliminating cancer cells without producing negative side effects [22–26].
Nanotechnology is one of the cutting-edge technologies used to develop a possible controlled-release drug delivery carrier with a great potential for delivering drugs efficiently. Nanoparticles provide target- and site-specific delivery because of their ability to pass through physiological barriers. The nanoparticles also enhance the effectiveness of drugs at low dosages and facilitate the management of chronic conditions by reducing adverse effects [27–31].
The novel tactics appeal to a wide range of industries, from materials engineering to biomedicine, since it allows for the design of functioning systems at the nanoscale. Nanotechnology in the field of medical science provides a platform for highly specialized medical treatments for the prevention, diagnosis, and treatment of illnesses, including cancer. Advancements in the field of nanotechnology in medicine over the last two decades have made it possible to incorporate a variety of therapeutic, sensing, and targeting agents into nanoparticles [32–37]. It is a revolutionary approach to designing, preparing, and using systems, gadgets, and structures by sculpting and modifying their dimensions at the nanoscale.
According to the National Nanotechnology Initiative (NNI), a government-sponsored US research and development initiative, the production of carriers, devices, or systems with sizes ranging from 1 to 100 nm, with the potential to reach 1000 nm, is referred to as nanotechnology [8, 35].
Traditional medicine has been practiced by the world since ancient times utilizing natural bioactive components. Due to their wide range of therapeutic benefits in reversing the progression of a disease, natural dietary phytochemicals have generated a lot of attention in this area. These bioactive phytochemicals found in a wide range of foods and beverages, are less toxic and effective as medicines. They can be incorporated into the host system's natural defense against parasites, viruses, and other external stimuli [38].
In certain circumstances, phytochemicals may especially help with the treatment of skin cancer. First, both the patient and the practitioner have easy access to precancerous and cancerous skin lesions. This assists in the design of topical treatments that can be administered just to the suspected malignant region of change while causing little harm to healthy skin. It may be necessary to provide a phytochemical orally to cure different internal organ tumors, which would have an impact across the body. Second, both doctors and patients can quickly assess if a skin lesion therapy was successful. Skin biopsies are very minimally invasive, although most malignancies need invasive pathological proof. Future investigations on the efficiency of phytochemicals in treating skin cancer may therefore be made simpler. The majority of local adverse effects may be readily identified using topical treatments, which may help patients experience less pain and lower their risk of developing more severe or long-lasting side effects.
Several phytochemicals, including epigallocatechin-3-gallate, capsaicin, silymarin, indole-3-carbinol, proanthocyanins, curcumin, resveratrol, luteolin, apigenin, and genistein may be found in fresh fruits, vegetables, roots, and herbs. They are thought to support cancer chemoprevention and treatment in a variety of ways [39–41].
The ongoing research prompted advanced knowledge in the therapeutic regimen, however, the condition is still fatal. In a way, current therapy limitations indicate the need for innovative therapeutics. Because conventional therapies have several limitations, effective alternatives must be found. Among the various therapeutic techniques, nanotechnology offers extraordinary potential on the molecular level through targeted interactions with cancer cells and suppression of their activity. Numerous compounds have already entered medical practice and have become the norm. The most exciting is combination therapy, which combines herbal treatment with the conventional drug into a unique formulation [42].
In this study, we provide an impression of the tremendous development of natural chemicals with synthetic drugs with excellent effectiveness and safety in skin cancer combination therapy accomplished by flexible nanotechnologies, which focus on solid-resistant skin tumor mechanisms. The section below discusses types of skin cancer, factors, and etiology associated with its progression, current therapeutic regimen, and the scope of nanotechnology in overcoming the treatment barrier.
Skin cancer is the commonest form of cancer and approximately one out of five people suffer from skin cancer anywhere in their lifetime. Low mortality cases were observed in the case of SC due to early detection and proper treatment. Cancer is the uncontrolled and unorderly growth of normal cells, and the capacity of losing the controlled growth of normal cells is termed contact inhibition of proliferation [43]. There are two main types of skin cancer which are specified as non-melanoma skin cancer and melanoma skin cancer and the former is further categorized into basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Non-melanoma skin cancer (NMSC) or keratinocyte skin cancer (KSC) is the most common form of skin cancer [44].
The most common cancer diagnosed in Australia, New Zealand, and North America is NMSC. Globally, according to Globocan's estimate, there were 1,042,056 new cases of NMSC in 2018, and 65,155 deaths, or almost 6% of deaths, were related to NMSC (mostly SCC). These numbers mirror those from Spain, according to reports [45]. NMSC skin cancer is a kind of skin cancer in which cells other than melanoma cells are affected by the cancer. The rate of occurrence of NMSC is increasing by 10% per year. The most common reason for NMSC occurrence is Ultraviolet (UV) rays have a high risk in persons with lighter shade. NMSC can also be developed due to Genetic mutation such as a mutation in certain gene families named CYP450, GST(Glutathione S-transferase), p53 [46]. There are several distinctive forms of NMSC which are caused by viruses such as verrucous carcinoma, Bowenoid papulosis, epidermodysplasia verruciformis, squamous cell carcinoma, Kaposi sarcoma, and the most common as well as high occurrence rate named Merkel cell carcinoma [47].
BCC is the most common type of malignancy of skin found in humans. The biggest risk is being exposed to sunlight. Due to its low fatality rate, BCC is not typically included in cancer registries; nonetheless, after analyzing data from insurance registries and official statistics in the United States (US), BCC incidence has been projected to reach 4.3 million cases annually [48]. The mortality rate is low but the morbidity rate is high due to local destruction of tissues [49]. Of all skin cancer patients, about 50% are suffering from BCC. BCCs are significantly more prevalent among Caucasians [50]. Generally, the cells in the epidermis concluded as keratinocytes in which basal cells are found in the bottom layer of epidermal cells are also a type of keratinocytes. It is the least destructive form of cancer that appears as light pinkish- or flesh-colored pearls same as bump or pinkish patches of skin. The major threat of having BCC is in the superficial layers including the face, hands, neck, legs, abdomen, or areas that are in direct exposure to UV rays emerging from the sun. It can expand throughout the body surface or can escalate to nerves or bones. The main causative agent for BCC includes (i) exposure to sun for a long time, (ii) immunity not able to cope with the cancer-inducing agents, (iii) beta human papilloma virus (HPV) and (iv) Human immunodeficiency virus (HIV) [51]. Cell growth is regulated by the patched/hedgehog intracellular signaling system, and continuous activation of this pathway results in the formation of BCC. The mutations that lead to abnormal hedgehog pathway activation and tumor formation are inactivating mutations of PTCH1 or activating mutations of SMOm. In a tiny subset of BCCs, a loss-of-function mutation in SUFU, an antagonistic modulator of the hedgehog pathway, also has been discovered. UV-specific abnormalities in the p53 tumor suppressor gene, which are present in half of BCCs, are another prevalent mutation [52].
Generally, it can be treated by radiation therapies or topical treatment including 5-fluorouracil or any combination [53]. Treatments are directed to local control only as it is very low metastatic in nature. The length of follow-up and the proportion of high-risk and recurrent cancers should both be taken into account when comparing the cure rates for treatments based on various research. For instance, BCCs' sluggish rate of growth makes it common to detect recurrences five years after the first diagnosis. A randomized controlled study with surgical excision found that the recurrence rate was 3% at 2.5 years and 12% at 10 years, respectively, and that 56% of recurrences happened more than 5 years after treatment [54, 55]. Figure 1 represents different molecular pathways involved in Basal cell carcinoma. The physiological parameters of various kinds of skin cancer are mentioned in the section below.
Illustration of different molecular pathways involved in Basal cell carcinoma. Adapted with permission from [50]
With an estimated 1 million cases each year in the US, cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in people. This estimate represents an increase in the number. Throughout the last three decades, the number of CSCCs has climbed from 50 to 300%, and by 2030, their frequency in European countries will be twice as high as it is now. It is the second most frequent type of skin cancer which is counted as 2.5 lakh people get effected with SCC in the US every year. In comparison to BCC, SCC has more occurrence risk as well as significant mortality rates (0.3–3.7%). According to estimates, the Caucasian population’s lifetime chance of having a CSCC ranges from 7 to 11% (9% to 14% for men and 4% to 9% for women) [56]. Although it typically displays benign clinical behavior, it has the potential to spread locally and metastatically. For CSCC, ten-year survival following surgery is above 90%, although it rapidly decreases when metastases appear. Lymph node metastases occur about 4% of the time, and mortality is close to 2% [56]. Squamous cell carcinoma is the secondary kind of skin cancer with the occurrence of 99% in all NMSCs patients and occurs in the keratinocyte cells of the outer/upper layer of the epidermis and seems like scaly patches of red firm bumps [57]. It is due to overexposure to UV rays and normally occurs in light-shady people. There are several factors that are responsible for SCC occurrence including light complexion, aging, burn scars, chronic skin ulcers, immune suppression, chemical carcinogens and majorly caused by UV rays [46]. Several molecular pathways have been linked to the development of CSCC. Early occurrences in CSCC, such as ultraviolet-induced P53 mutations, cause significant genomic instability. As we will see later, CSCC has the highest mutational burden of any solid tumor, which may have therapeutic implications. Thereafter, oncogenes like RAS and other suppressor genes like CDKN2A and NOTCH undergo additional genetic alterations. Epidermal growth factor receptor (EGFR) upregulation is eventually caused by the activation of several signaling pathways, including the Nuclear factor kappa B (NF-kB), Mitogen-activated protein kinase (MAPK), and phosphoinositide 3 kinase (PI3K)/Akt/mammalian (or mechanistic) target of rapamycin mTOR pathways. Alterations to the epigenome may also occur [56, 58–63]. The pathways are represented in Fig. 2 . The mainstay of treating CSCC is surgery, though radiation is occasionally used as well. But some individuals with locally progressed and metastatic CSCC might gain from systemic therapies [64].
Representation of therapeutic landscapes involved in Cutaneous cell carcinoma. Adapted with permission from [56]
Melanoma are aggressive malignant tumors that arise from melanocytes. Melanocytes are located in the epidermis' basal layer. A buildup of genetic alterations that activate oncogenes, deactivate tumor suppressor genes and hinder DNA repair when organisms are exposed to ultraviolet radiation. This mechanism may result in unchecked melanocyte growth and ultimately malignancy [65]. An estimated 70,000 people in the US were diagnosed with malignant melanoma in 2007 in which most of them were cured but even so, there is approximately the count of 1000 people that died each year from melanoma skin cancer. Immensely 75% of mortality cases were of malignant melanoma alone in all skin cancer-suffering patients [66, 67]. It is an odd but more deliberate kind of cancer in comparison to NMSC. So, the early spotting of the disease is much more important to cure the disease properly with less damage [68]. For detecting melanoma carcinoma physically, we can follow the ABCD rule which includes firstly, Asymmetry – both sides of the wound don’t look alike, Secondly, Border-irregularity – edges of the skin cells suffering from melanoma are not well ordered or systematic or even, Thirdly, Color – this carcinoma is an amalgam of colors, including brown, black, tan, blue or red, and at last, Diameter – the diameter of the cancerous area is generally greater than 6 mm (approx. a size of pencil eraser), but variation in size may be possible [66].
Figure 3 represents different types of skin cancer.
Illustrates different types of Skin cancers
The prognosis for individuals with cutaneous melanoma depends on the depth and location of the initial tumor, as well as whether or not they have localized or distant metastatic disease. For their distinctive histologic characteristics, the four main subtypes of invasive cutaneous melanoma are categorized as follows: superficial, nodular, lentigo malign, and acral lentiginous. Superficial melanomas are the commonest of subtypes accounting for about 75% of melanomas. It appears as a mole-like pigmented skin lesion that has changed in size, shape, or color. In women, it is manifested on the legs while in men it typically manifests on the trunk [69, 70]. Nodular melanoma accounts for about 15- 30% of melanoma cases. It is an aggressive, vertically developing melanoma. As it lacks a radial growth phase, it expands in depth more rapidly than in width. Because of this, it could take more time for someone to become suspicious about the lesion. Nodules that are pedunculated or polypoid in shape are the typical presentation of nodular melanoma. Older people's heads and necks are more likely to develop nodular melanomas, which are hard, symmetrical, evenly pigmented papules or nodules that can ulcerate and bleed [71].
The second most prevalent subtype of melanoma is lentigo malign (LM). It often appears as a small, flat, tan, irregular-bordered, asymmetric macule on sun-exposed areas. With time, the macule grows larger and starts to change color. Hutchinson's freckle, also known as lentigo malign, begins as a pigmented macule that grows slowly and may stay in place for many years. These melanomas are substantially more prevalent in adults over the age of 60 and are commonly referred to as “senile freckles". These may progress quickly once they become invasive. They frequently have poor definition and variable pigmentation. The way LM is managed is always changing. If available, the first course of treatment is surgery, followed by radiation, and in patients where surgery is not an option imiquimod cream is used [72, 73].
Acral lentiginous melanomas (ALM) are a rare subtype of melanoma. It makes up about 2 to 3% of all melanoma diagnoses, making it the least prevalent melanoma subtype. It generally occurs on soles, toes, palms, fingers, and nail beds. Unlike other types of melanomas, it is not linked to sun exposure. It is the most prevalent subtype of melanoma diagnosed in people of Asian or African heritage and tends to be more advanced at presentation due to delays in detection. Due to the complexity and functional significance of the hands and feet, surgical treatment is challenging, and repair is frequently required after resection. The prognosis for people with this type varies with disease stage and is typically poorer than with other melanoma subtypes. Patients with advanced ALM are being investigated for response to newer therapeutic modalities, including immunotherapies and targeted drugs, with some encouraging early findings [74, 75].
Skin cancer progression involves a complex interplay of genetic, molecular, and environmental factors that lead to the transformation of normal skin cells into cancerous ones. it can happen because of many reasons including direct exposure to UV radiation on exposed areas of skin, immunogenic skin problems, DNA damage due to various reasons, skin color, sun tanning bed, and many more. Several etiologic agents that cause skin cancer were described below.
Ultraviolet radiation is the predominant root-cause of skin cancer. It is responsible for more than 80% of skin cancer cases [76]. There are three types of UV radiation: UV-A, UV-B, and UV-C. UV-A and UV-B make up the majority of the components of sunlight (90% and 10% respectively). The atmosphere primarily absorbs UV-C rays. As UV-A has a longer wavelength (320–400 nm), it can enter the dermis and produce free radicals there. The epidermis' stratum basale is reached by UV-B, which has a shorter wavelength (290–320 nm) and induces the synthesis of thymine dimers. Both UV-A and UV-B influence the development of cancer, but UV-A is regarded to be more important. UV light damages cells induces apoptosis, and hinders DNA repair processes, all of which result in DNA mutations [77]. UV radiation can destruct the DNA and cause genetic mutations, which further damage the skin cells and cause skin cancer [78]. UV exposure causes DNA damage that results in mutation and lowers the host immune system's capacity to detect and eliminate cancerous cells, which together create a two-fold mechanism that causes carcinogenesis. There are various factors that can guide the quantity of UV radiation reach to the earth's surface and can control its harmful effect counting as ozone depletion control, gratitude, latitude, less use of products having CFC (chlorofluorocarbon), keeping control of climatic change and many more. UV radiation is a remarkable and universal physical cancer-inducing agent in our natural surroundings [79]. UV rays are a major etiological aspect of basal cell carcinoma [80].
Skin cancer is the most prevalent malignancy in the USA, accounting for 35–45% of all neoplasms in Caucasians, 4–5% in Hispanics, 2–4% in Asians, and 1–2% in Blacks [81]. It is experimentally proved that white Caucasian skin is more perilous or unsafe than pigmented skin for skin cancer [79] for both melanoma and non-melanoma. The greater melanin in the epidermis, which screens twofold as much UV light as that in Caucasians' epidermis, is principally responsible for the lower incidence of skin malignancies in darker-skinned races. Darker-skinned populations have large and more melanized melanosomes which absorb and disperse energy higher efficiently than Caucasians' smaller, melanosomes [82]. Skin cancer in non-White people frequently manifests at a later stage, which makes the prognosis poorer than in White individuals. Skin cancer patients of color experience higher morbidity and fatality rates than white patients, which may be attributed to a lack of awareness, more advanced diagnosis, and socioeconomic issues including barriers to care [83]. NMSC has much more incidence rates in comparison to MSC in Caucasian skin cancer patients [84]. In dark-skinned persons, squamous cell carcinoma, a kind of NMSC is most common, whereas in Caucasians basal cell carcinoma, another class of NMSC is most common [80, 85]. All racial groupings generally receive the same treatment [81].
Immunosuppression has a strong probability of causing skin cancer these days specially NMSCs. White solid organ transplant recipients (SOTRs) are 50% more likely to develop skin cancer. The average time from transplantation to diagnosis is three to eight years, and more than 90% of tumors are BCC or SCC. Multiple tumors are frequently discovered in SOTRs, and these tumors typically exhibit greater aggressiveness than those found in the entire population [86]. Melanomas account for a larger percentage of skin malignancies in the pediatric SOTR group than in adult receivers (12% vs. 5% of all skin cancers, respectively) [87]. When an organ transplant takes place in any individual, the chances for the occurrence of NMSCs gradually increase, in HIV patients, or patients having chronic lymphocytic leukemia, etc. the chances of skin cancer are much more higher [88]. Immunosuppressive medicines accelerate cutaneous carcinogenesis. SCC and BCC occurrences are 65-fold to 250-fold and tenfold higher in transplant recipients than in the general population, respectively, and the incidence of skin cancer keeps increasing years later [89]. It is important to note that T-cell immunosuppression is highly elevated in skin cancers. Neoepitopes, tumor-associated antigens, and/or viral oncoproteins are assumed to be the sources of the skin malignancies' antigenicity. Tumor cells interact with immune system elements that are functioning to impede the proliferation and metastasis of melanoma throughout the melanomagenesis process. Although Breslow thickness and lymph node metastasis are still regarded as poor prognostic indicators, melanoma cells' tendency to infiltrate distant organs likewise relies on how they interact with other cells in the tumor microenvironment (TME) and the manner in which the immune system responds. While the location, composition, and density of TILs around melanoma cells favorably associated with survival and a lower risk of metastasis, their properties affect the prognosis [90].
In this scenario, the dominant immune cell groups in close proximity to melanoma cells include both CD8 + and CD4 + T-cells. However, recent research indicates that additional molecules might also have a potential correlation with prognosis. These molecules encompass the reduction of p16 expression, the transition between M2/M1 polarization in macrophages, as well as the levels of immune checkpoints, such as V-domain Ig suppressor of T-cell activation (VISTA) and PD-1 [91].
Melanomas have an abnormal overexpression of tumor-associated antigens (such as MART1/MLANA, MAGE antigens, and NY-ESO1), which makes them vulnerable to T-cell death as T cells that recognize such antigens are able to bypass negative thymic screening. The majority of skin malignancies, including BCC, malignant melanoma (MM), cSCC, and virus-negative MCC (VN-MCC), also have very high tumor mutational burdens (TMB), which are primarily triggered by UV-signature mutations and contribute to the development of novel tumor-associated epitopes, according to high-throughput sequencing techniques. The three solid tumors with the greatest TMB among those studied thus far are cSCC, VN-MCC, and melanoma. The notion that neoantigens significantly contribute to immunogenicity in the majority of malignancies is supported by the finding that TMB has proven a reliable predictor of immunotherapy response, both within and across tumor types [63, 92–94].
The immune system can also help in accelerating, modifying, and curing skin cancer [95]. The risk factor of cutaneous squamous cell carcinoma is enhanced rapidly in organ transplant patients including kidney, liver, heart, and diabetic nephropathy, etc. [96]. In one cohort study, it was found that during follow-up of patients with transplantation, 1,610 transplant recipients acquired 3,406 cancers. They included 668 patients with 2,231 SSC and 1,036 patients with 1,175 cancers other than SCC. Regardless of the kind of graft, the risk of cancer excluding SCC tripled after 20 years, whereas the risk of SCC remained consistent. Part of this increase in risk was caused by a subgroup of patients who were generating new SCCs at an accelerated rate [96].
Indoor tanning is the crucial cause for the occurrence of non-melanoma and melanoma skin cancer together due to increased utilization of indoor tanning which is the major source of artificial UV radiation these days [97]. The use of indoor tanning is increasing in the mountain regions due to several health sequel, and among youth the use of indoor tanning beds is also on the rage, which takes up the cause of death-dealing melanoma and eye problems [98]. One of the systematic reviews from the International Agency for Research on Cancer clearly displayed a link between tanning bed use and a significantly higher risk of melanoma. This also led to the ban on artificial tanning beds for commercial purposes in Australia [99]. According to later research, banning sunbeds would prevent one out of six melanomas among Australians between 18 and 29 years of age [100].
Age is also a factor behind the occurrence of skin cancer i.e., the older population has more risk of occurring skin cancer than younger and middle age group persons. Aging is the culmination of all the changes that occur to people through time, including psychological, social, and physical changes. Aging is one of the most significant identified risk factors for the majority of human diseases, including cancer. Cells are more likely to experience somatic mutations after several generations of replication, which could result in unchecked cell growth [101]. As evidence, the incidence rate in women greater than 40 years of ag shows a linear increase in BCC incidence rates [84].
There is various evidence that reveals that viruses also have a compelling or paramount role in the occurrence of skin cancer. In 1908, an experiment done by Ellerman and Bang, who were Danish scientists, demonstrated that the Rous sarcoma virus is the cause of the occurrence of leukemia in chickens. Afterward, there were many other observational authentication claims that viruses can also be the causal agent for skin cancer [102]. It has been established that skin infections mediated by β-HPVs have also been connected to cutaneous squamous cell carcinomas [103]. A viral origin is suggested by the greater frequency of keratinocyte carcinomas in people with compromised immune systems. The causal significance of HPV in the emergence of skin cancer is demonstrated through a transgenic mouse model. Skin cancer appears spontaneously in mice that express the HPV8 region and the human keratin-14 promoter simultaneously [76]. Although a meta-analysis appears to have proved that β-HPV infection is a risk factor for the development of SCC in healthy individuals, the role of β-HPV in the development of cSCC in the general population is still debatable [104]. The HHV8 human herpesvirus is the cause of Kaposi's sarcoma (KS). Age (risk increases with age) and immunocompromised status (induced by HIV, medications, or the host's genetic characteristics) are risk factors for the emergence of KS and HHV8-related malignant lesions [105].
Cancer arises due to irregular cell growth and division, which lacks synchronization with the adjacent healthy tissues. This condition results from epigenetic and genetic changes that contribute to the transformation into a neoplastic state. Over recent years, numerous essential molecular pathways associated with the initiation, advancement, and proliferation of melanoma have been revealed.
The WNT signaling pathway governs critical processes, including determining cell polarity, cell fate, migration, and proliferation. The WNT protein family consists of glycoproteins that are secreted and bind to Frizzled receptor (FZD) proteins, which have seven transmembrane segments. This binding triggers intracellular signal transduction. Upon WNT-FZD binding, three potential signaling pathways become active: (a) a canonical pathway dependent on β-catenin; (b) a non-canonical pathway independent of β-catenin for cell polarity signaling; and (c) a pathway dependent on both WNT and protein kinase-C (PKC) [106, 107].
All G-protein coupled receptors (GPCRs) share a common core feature consisting of seven alpha-helices that traverse the cell membrane. This structural arrangement enables them to be influenced by various agonists or antagonists. When GPCRs are activated, they typically oversee cellular functions by unleashing the signaling capabilities of inactive heterotrimeric G-proteins. These dormant heterotrimers comprise a Gα subunit bound to guanine diphosphate, which maintains a strong affinity for a functional Gβγ monomer. Upon being triggered by a compatible ligand or signal, a GPCR triggers the replacement of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the Gα subunit. This results in the Gα subunit having a reduced affinity for Gβγ. Consequently, this modification leads to the separation of the subunits or reconfiguration of the heterotrimers, enabling Gα and Gβγ to interact with and regulate a diverse array of effector molecules, which is continuously expanding. Ultimately, the specific G-protein coupling of each receptor dictates the type of downstream signaling targets it engages with. Although GPCRs have conventionally been associated with the activities of specialized, non-dividing cells, they are also present in dividing cells, contributing to processes such as embryogenesis, tissue reconstruction, inflammation, angiogenesis, regular cell proliferation, and even cancer [108, 109].
The mitogen-activated protein kinase (MAPK) pathway holds significant importance as an intracellular signaling route. Activation of this pathway takes place in normal physiological conditions when growth factors externally bind to receptor tyrosine kinases (RTKs).
The role of MAPKs is to facilitate the transmission of signals that regulate various intracellular processes, including immediate hormonal responses, embryonic development, cellular differentiation, proliferation, and programmed cell death (apoptosis). For the MAPK pathway to be activated, an interaction between an RTK and its corresponding ligand is crucial. This interaction triggers the activation of rapidly accelerated fibrosarcoma (RAF) components (BRAF, ARAF, and CRAF), which are integral to the pathway [110]. This series of events set off a chain reaction within the cell, resulting in increased cellular growth, improved cell survival, and the prevention of apoptosis. In the absence of an RTK-ligand interaction, RAF kinases remain in their inactive state without undergoing phosphorylation, leading to no signal transduction. However, when an RTK and ligand interact, the phosphorylation of RAF takes place. This leads to the activation of BRAF and CRAF serine/threonine kinases, which then act as downstream mediators. Once activated, RAF forms homo- or heterodimers that interact with and phosphorylate mitogen-activated extracellular signal-regulated kinase (MEK). MEK, in turn, phosphorylates and activates mitogen-activated extracellular-signal-regulated kinase (ERK). The activation of ERK plays a pivotal role in oncogenesis by promoting cell growth and differentiation. Additionally, activated ERK is responsible for initiating a negative feedback loop at various levels of the MAPK pathway to regulate its activity. Furthermore, RTK-ligand interactions can also trigger the activation of other intracellular pathways, such as the phosphatidylinositol-3-kinase (PI3K) pathway [111, 112].
Oncogenic RAS, a participant in the MAPK pathway as discussed earlier, also functions as a positive regulator upstream of the PI3K pathway. Consequently, the activation of RAS transcription triggers the downstream activation of two distinct yet interconnected pathways such as the PI3K-AKT signaling pathway and the RAF–MEK–ERK pathway. While both pathways contribute to cell proliferation, dissemination, and survival, the PI3K-AKT pathway additionally stimulates anabolic processes, while the RAF–MEK–ERK pathway predominantly facilitates proliferation and invasion. One of the inhibitors of the PI3K pathway is the enzyme phosphatase and tensing homolog deleted on chromosome 10 (PTEN). PTEN catalyzes the de-phosphorylation reaction of phosphatidylinositol 3,4,5-trisphosphate (PIP3) back to phosphatidylinositol 4,5-bisphosphate (PIP2) through its lipid phosphatase activity. This action leads to a decrease in phosphorylated AKT (p-AKT) levels and subsequent inhibition of the PI3K signaling pathway. Additionally, PTEN has the ability to target and dephosphorylate other proteins, such as focal adhesion kinase (FAK), which in turn curbs focal adhesions and reduces cellular migration. Interestingly, PTEN is also believed to interact with the MAPK signaling by dephosphorylating adapter proteins, resulting in diminished phosphorylation of MEK1/2 and ERK1/2. The loss or inactivation of PTEN leads to unregulated signaling through the PI3K pathway. Notably, the absence of tumor suppressor genes located on chromosome 10, including PTEN, is detected in a considerable portion (30%–60%) of non-inherited melanomas. Crucially, the lack of PTEN expression has been noted in around 30%–50% of established melanoma cell lines and 5%–20% of primary melanomas. Remarkably, mutations in both BRAF and PTEN have been frequently observed to co-occur at high rates in melanoma, whereas NRAS mutations have been found to be mutually exclusive with BRAF and PTEN mutations [113–115].
Solid tumors start at the site where the level of oxygen is frequently reduced due to the enhancement in oxygen diffusion interspaces i.e., the distances among cells and vasculature. The oxygen deficiency also occurs due to additional uptake of oxygen by the proliferative cancerous cell which causes hypoxia in the surrounding environment which accelerates the mechanism of cell apoptosis [116]. At the tumorous site, the accumulation of mast cells occurs to tackle the damages and impairment. Mast cells recruit various kinds of chemokine behaviors which play a crucial role in defensive mechanisms [117].
SCC or BCC expands as a precancerous lesion named actinic keratosis, which is also called keratinocyte intraepidermal neoplasia, very general in UV-exposed regions and looks like reddish macules which are further enfolded by yellowish scales. There is the presence of a typically large nucleus including hyperchromasia, dyskeratosis, and mitosis at the region of actinic keratocytic in the epidermal layer. The pathogenic pathway which shows involvement in skin cancer is shown in Fig. 4 as such; Protein patched homolog 1 (PTCH1) plays the tumor-conquering action which encodes a protein receptor termed Sonic Hedgehog (SHH), which causes the loss of PTCH1 functionalities that impacts on working of G-Protein coupled receptor as decreasing the suppression of intracellular signaling which Smoothened (SMO) G-Protein coupled receptor. glioma-associated oncogene transcription factors (GLI) were targeted by SMO, whether a mutation in PTCH1 induced encouraged activation of target genes [118].
Diagrammatic representation of the detailed mechanism of tumor vascularization
We must prevent skin cancer in various ways which must be effective in controlling and stopping the spreading and rising level of cancer patients, such as (i) By increasing the awareness of sun exposure and its harmful effects in public and guiding the patients on an individual basis [119], (ii) By avoiding indoor tanning and never use UV beds, (iii) By applying broad spectrum range of sunscreen having a Sun protection factor (SPF) range equal to or greater than 15 [120], (iv) By avoiding to getting sunburned, (v) By examining your whole body from head to toe at every month, (vi) By visiting the dermatologist at least one in a year for examining the skin professionally, (vii) By being in shade mostly between 10 AM to 4 PM [121]. Treatment is depended upon the type and stage of skin cancer and the circumstances by which it can be diagnosed. There are different treatments regimes that are either under trial or approved by US-FDA which tabulated in Table Table1 1 .
The approved and currently under trials treatment modalities for the cSCC. The Table was modified from Mårten et al. (https://www.nature.com/articles/s41568-023-00583-5)
EGFR inhibitor + Chemotherapeutic agents (Cetuximab + 5FU + Cisplatin)
Abbreviations: These treatments modalities are currently in clinical use a part of different trials or an approved modality in the United States
cSSC cutaneous squamous cell carcinoma, PD1 Program Death 1, EGFR Epidermal growth factor receptor, NSCLC Non-small cell lung cancer, HNSCC Head and neck squamous cell carcinoma, CTLA-4 Cytotoxic t-lymphocyte associated protein-4
Surgery is the method in which the cancer cells are treated with a combination of chemotherapeutics, and excisional removal of tissues with the use of certain surgical instruments are used for the procedure. The traditional method of removing cancerous cells by using a scalpel to a certain depth is also a type of surgery. Different kinds of surgical methods are used to treat cancerous tumors which are described as such [133].
In simple excision, the area belonging to the tumor are totally cut and removed along with some normal cells or tissues of the body followed by stitching of the area of the incision, then the removed tissues by a dermatopathologist, were sent to the laboratory for assessment the tissues for the confirmation that the whole tumor area has been removed [134]. A markup in fusiform shape is advisable which precludes the excess skin along the ablation [135].
It is the treatment of choice for high- risk nonmelanoma skin cancer. It is usually performed when the cancer is recurrent type and when tissue conservation is needed. The surgery is an outpatient one, which is preferentially used for large area tumors which is the amalgamation of the removal of the tumorous tissue followed by microscopic analysis during the surgery takes place. By analyzing the skin in stratified form the little damaged skin is also affected during the removal of the tumor (Fig. 5 ) [136, 137]. And further, the area is assessed for the presence of any additional tumor tissues or cells at the excised location [138]. After that, a thin portion of the underlying tissue is extracted and histologically analyzed by a frozen section to see if it is tumor-free. If not, additional surgical layers are excised until no microscopic signs of a tumor are present. The patient stays in the hospital while tissue samples are examined following the one-time surgery. The fundamental benefit of Mohs surgery is that it maximizes the preservation of healthy tissue while providing exact microscopic control of the whole tumor margin. Retrospective investigations have discovered a 97% 5-year primary tumor cure rate and a 90% 5-year recurrence cure rate. This contrasts with 77% for recurrences and 92% for primary tumors with other methods [139, 140].
Procedure for Mohs Microscopic surgery used for the removal of the tumor from the skin. Adapted with permission from [141]
In this technique, the health specialist removes the tumor area after desensitizing the area by applying anesthetic locally and sweeping out the tumor tissues with an instrumental tool called ‘curette’ which has sharp edges and a tiny scoop. Then, to stop any further bleeding, they use a probe by using electricity or electric current. Following that, one has to follow the same procedure several times which is followed by bandaging the treated area which leaves a light pink or white scar. This technique is used only for the tumor which lies on the upper layer of the epidermis mostly for BCC and SCC [134]. A controlled study compared the cure rates of low-risk SCC at one year by ED&C to those by surgical excision in a dermatological clinic at a Veterans Administration teaching hospital. A second study looked at the success rate of curettage and electrodesiccation for low- risk lesions in a private clinic. The first study did not show any significant difference between ED&C ( whole of 14 patients treated successfully) and Surgical excision (15 of 16 patients treated successfully and 1 recurrence), while the second study showed that 106 of 106 patients were treated successfully by ED&C as compared to 95% arbitrary cure rate [142]. This proved the efficacy of the ED&C method in the treatment of low-risk BCC.
It is a technique in which an inactivated topical medication is applied to the affected area, and the area gets further activated by exposure to a certain wavelength of light. The main component of photodynamic therapy (PDT), a way of treating malignancies, particularly cancer, is the impact that photochemical reactions have on biological tissues. The initiator of these processes is light energy [2]. The three key elements of PDT are oxygen, light, and photosensitizer. It is clear that none of these substances are harmful when taken alone, but when combined, they start a photochemical process that results in the production of singlet oxygen, a highly reactive substance, as well as a number of free radicals. By causing profound functional and structural changes in the cellular membrane and activities taking place inside of them, this singlet oxygen activates the cytotoxic activity, which is a unique mechanism of damage to critical cell functions and ultimately leads to the death of these cells [143] as shown in Fig. 6 . In the instance of skin cancer the drug may be applied directly on the skin in liquid form [144]. Photodynamic therapy and photothermal therapy are two different kinds of therapy for healing skin cancer in which the former results in chemical damage at the localized target site whereas the latter results in thermal damage at the localized cancerous lesson site. Photosensitizers play a key role in photodynamic therapy due to killing or inactivating cancerous cells. Whereas, in addition, the exogenous photothermal contrast agents are not having any important role but can enhance the efficacy and efficiency of the therapy [145]. A randomized intraindividual comparison study to assess the effectiveness and safety of methyl amino levulinate (MAL)-PDT vs. Imiquimod (IMQ) 5% in the treatment of patients with field alterations to prevent the development of new NMSCs was carried out. It was found that the trial was completed by 44 patients. There was no statistically significant distinction in the creation of new NMSCs at any stage during the follow-up period between MAL-PDT and IMQ, hence there was no difference with regard to the primary endpoint. Both treatment plans were well-tolerated and safe. MAL-PDT was preferred by patients in relation to the technique, response rates, and future options [146]. For its members, the American Society of Dermatologic Surgery (ASDS) regularly creates consensus documents on a range of topics concerning surgeries related to dermatology. Photodynamic treatment (PDT) has undergone numerous advancements, and it is now widely used to treat a range of skin disorders. According to the ASDS, photodynamic treatment is quite efficient for treating inflammatory acne vulgaris, precancerous lesions, and superficial nonmelanoma skin malignancies [147].
An illustration of the effector mechanism in photodynamic therapy. 1) Activation of the photosensitizer by external light of a specific wavelength results in the singlet state, which is followed by the creation of reactive oxygen species (ROS), which is the main cause of the apoptosis of tumor cells. 2) Photodynamic therapy activates the immune system, releasing inflammatory mediators like IL-6, IL-1, and TNF-alpha, heat shock protein (HSP), and DAMPs (Damage Associated Molecular Patterns), which cause tumor cells to die
Various studies have recorded the use of PDT to be an efficacious treatment for BCC [148, 149]. For low-risk basal cell carcinoma (BCC), photodynamic therapy (PDT) is a well-established treatment option [150]. Many nations have approved topical PDT as a therapy for BCC. Although it has not yet received USA approval. A recent evaluation found interest in its use as a "off-label" treatment. ALA and MAL are approved prodrugs for the topical PDT therapy of BCC [151]. Despite reports that the usage of ALA and MAL cause different pain levels, with MAL-PDT causing less pain, a cohort study revealed no discernible difference [152]. With a three-month follow-up, the licensed MAL-PDT protocol employs a cycle of two treatments separated by a seven-day gap [150, 153]. The suggestion to consider a treatment with topical PDT is often restricted, i.e., in the case of nBCC, to thin (2 mm) nBCC, because the ability to penetrate both the prodrug and light decreases with the growing depth of the BCC lesion [153].
As topical PDT has a lesser clearance rate than surgical BCC treatment and has a limited depth of penetration for both the prodrug and the stimulating light, topical PDT is not advised for high-risk BCC subtypes [148]. However, in some circumstances, if a low-risk BCC subtype spreads periphery from a high-risk subtype, topical PDT may serve as an adjuvant therapy to surgery. PDT treatment may be utilized before surgery in order to streamline the surgical procedure or, more frequently, after margin-controlled surgery in cases where a low-risk BCC region remains and the morbidity from further surgery outweighs the risk of a potential recurrence after PDT [154, 155].
PDT treatment is constrained by the radiation's depth of penetration, which varies with the BCC's depth and pigmentation as well as with the radiation's wavelength. Some of the recent photosensitizers can expand the PDT treatment window into the near-infrared (NIR), potentially opening the door to deeper tissue penetration. They can also penetrate pigmentation, which reduces the PDT treatment window's effectiveness by quenching ROS produced by PDT and by absorbing incident radiation [150].
The results of various clinical randomized trials as mentioned in a systematic review [156] shows that the use of topical PDT for low- risk BCC is an effective treatment. For nBCC there were 3 trials with MAL prodrug and it showed a clearance rate of 73% [157], 91% [158, 159], and 88% [160] after 3 years. One study was for nBCC with ALA and it showed 93% clearance after 3 years [161, 162]. Three studies were for sBCC which showed clearance at three years of 90% [163], 87% [164], and 82% [165–167].
A clinical trial (NCT03573401) titled “A Randomized, Double-Blind, Vehicle-controlled Multicenter Phase III Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) and BF-RhodoLED® in the Treatment of Superficial Basal Cell Carcinoma (sBCC) with Photodynamic Therapy (PDT)” is being conducted at multi-centers (15 sites) to compare the safety and effectiveness of photodynamic therapy (PDT) for superficial basal cell carcinoma (BCC) using the drug Ameluz® and the PDT-lamp BF-RhodoLED® to the corresponding placebo treatment [168]. This kind of trial would be the perfect opportunity to conduct additional research on any refractory or recurrent tumors that may develop and to correlate these findings with patient characteristics so as to both improve the treatment of such tumors and, possibly, screen patients before they undergo PDT and provide them with personalized information about the possibility of treatment failure. By doing so, PDT's cosmetic advantages may be made more publicly known and new knowledge about the technique's potential use to the treatment of others, more dangerous tumors could be gathered.
The absence of standardized treatment procedures or results data makes it difficult to employ PDT for SCC clinically. Although MAL and red- light illumination have been utilized in the majority of published trials for SCC, ALA and blue-light illumination (ALA-PDT) is the most popular method of PDT administration in the United States. Furthermore, it is unknown if additional tumor or therapy factors influence PDT response. Data on whether tumor size [169–172] or anatomic location [173, 174] affect response are inconclusive. According to varying reports, the number of PDT treatments and the incubation period for ALA both have an impact on the removal of malignant and premalignant lesions [169, 175, 176].
In 58 patients with 68 primary SCCis lesions that were treated with ALA-PDT and blue light illumination, according to a retrospective review. The initial full response rate following PDT was 77.9%; it was unrelated to the quantity of PDT treatments. The position on the face, a tumor diameter of less than 2 cm, and a longer ALA incubation period were significantly linked with the response on multivariate analysis. Lesions treated with an incubation period of no more than three hours exhibited a 53.3% response, while extended incubation times resulted in an 84.9% response. SCCis recurred later in 7 of 53 instances (13.2%), with a median interval of 11.7 months [177].
Repeated cycles of PDT have been proposed to prevent the development of carcinomas in patients at high risk with many lesions. Field therapy of lesion precursors with topical fluorouracil has been found to lower the incidence of eventual SCC. In this way, PDT may address preexisting SCCis and prevent new lesions, however, further research is needed to fully understand this effect [178, 179].
PDT is a possible alternative palliative therapy for individuals with advanced melanoma since it is minimally invasive and has few adverse effects. The most important challenge is to overcome melanoma resistance, due to melanosomal trapping, the presence of melanin, enhanced oxidative stress defense, defects in the apoptotic pathways, immune evasion, and neo-angiogenesis stimulation [180]. Chemotherapy, immunological treatment, or a photosensitizer that is designed for a theranostic approach with increased efficacy can all be used in conjunction with PDT to treat melanoma.
Baldea et. al. reported that while PDT on human and mouse melanoma cells using various procedures significantly increased apoptosis, necrosis, tumor growth halt, and prolonged animal life in experimental settings, it rarely resulted in full recovery and/or was accompanied by recurrence and side effects. According to the clinical data, PDT caused choroidal melanoma and cutaneous melanoma metastases to regress [180].
An article demonstrated a different method for treating melanoma by combining traditional PDT with electroporation. Through temporary membrane holes, the method improved the photosensitizer's intracellular trafficking. In vitro, the technique proved more effective than PDT alone at inducing apoptosis in human melanoma cell lines that were both amelanotic (C32) and melanotic (MeWo) [181].
A few research [182] suggested theranostic nanoparticles to treat melanoma. A complex nanoconstruct with increased tumor targeting and anti-melanoma activities against a melanoma cell line (A375) in vitro was made using a single-walled carbon nanotube carrier and zinc monoamino phthalocyanine, which was additionally connected to folic acid [183]. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier to construct a multidrug nanoparticle that delivered doxorubicin, a chemotherapeutic agent, and methylene blue, a photosensitizer for PDT. The melanoma cells' drug accumulation, as well as the antitumor effectiveness, were both raised by the nanoparticles [184]. Fraix et al. reported using two chromo fluorogenic components to visualize the medication administration while also delivering photosensitizers to melanoma cells using biocompatible polymeric nanoparticles. Through the production of both singlet oxygen and nitric oxide, this method improved tumor cell killing [185]. Clinical studies revealed that topical IMQ (a toll-like receptor agonist) and PDT (ISPI) together enhanced PDT's overall anti-melanoma effects [186–188]. According to current applied research, actively targeted PDT unconventional treatments do seem to have a chance of enhancing treatment for metastatic melanoma.
In the fight against cancer, photothermal therapy (PTT), which transforms light energy into heat energy, has emerged as a new research hotspot. PTT's simple operation, brief treatment period, and quick recovery make it highly valuable for research [189, 190]. Following administration of the photosensitizer for a variable amount of time, light of a fixed wavelength is focused precisely on the target lesion, which causes the selective excitation of the photosensitive agents and the subsequent induction of photophysical and photochemical actions for the treatment of cancer.
In PTT, photothermal agents accelerate the localized heating of cells and tissues. These substances absorb energy from photons and change from their ground singlet state to an excited singlet state when exposed to the light of a particular wavelength. A heat-shock reaction begins when a tissue's temperature rises to 41 °C, which then triggers a series of quick changes in gene expression patterns, including the production of heat-shock proteins, to lessen the effects of the original thermal injury. When the temperature rises to 42 °C, irreversible destruction of tissue takes place; after being heated for 10 min to a temperature between 42 °C and 46 °C, tissues experience cell necrosis. Cells quickly perish at 46–52 °C due to microvascular thrombosis and ischemia. Due to protein denaturation and plasma membrane disintegration, cell death occurs very instantly at tissue temperatures > 60 °C, which are often reached with PTT [191, 192]. Due to the fact that cancer cells often have a low tolerance to heat, PTT is a promising treatment. Additionally, external laser irradiation with a dosage that may be adjusted enables the selective eradication of different malignancies while minimizing harm to the nearby nonmalignant tissue [193].
Although other delivery methods are possible, such as oral delivery (for example, ALA, which is more convenient for patients but is associated with concerns over inter-patient variability in bioavailability and pharmacokinetics, photosensitizing agents are typically administered in clinical settings through intravenous or topical application. The pharmacokinetics and biodistribution of photosensitizers have been demonstrated to vary depending on whether they are delivered intravenously or intraperitoneally in preclinical investigations on rodents [194].
Large-scale clinical trials using photothermal therapy (PTT) agents, which can be utilized to boost the effectiveness of localized light-based heating and ablation of cancer tissues, have not yet been conducted; laser ablation without PTT drugs has, however, been used therapeutically [145].
The biggest challenge with PTT is the systemic diffusion of PTAs in the body and non-precision laser irradiation, which might have detrimental side effects on healthy tissues surrounding tumors [195]. Attention has been focused on the creation of nanosized photothermal agents (NPA), which can accumulate in tumors through enhanced permeability and retention (EPR) effects and active targeting [196, 197]. This would thus reduce the off- site side effects. To present, numerous NPAs, including metal nanomaterials (gold and platinum), semiconductor nanomaterials (copper), nanomaterials made of carbon (graphene and carbon nanotubes), and conduction of polymers (polyaniline and polypyrrole), have been created for improved PTT-based cancer treatment [198–200].
Han et. al. prepared bimetallic hyaluronate modified gold-platinum nanoparticles for photothermal therapy of skin cancer. It was found that these nanoparticles were noninvasively transported into deep tumor tissues in comparison to traditional PTT through injection, and they ablated the targeted tumor tissues by NIR light irradiation [201]. In another study, nanographene oxide- hyaluronic acid conjugate was used for photothermal ablation therapy for melanoma skin cancer. The study confirmed the feasibility of using transdermal photothermal ablation therapy using this conjugate [202]. Bonamy et. al. studied the internalization, trafficking, and efficiency of green gold nanoparticles (gGNP). The study showed that glucose-stabilized gGNP allows for fast internalization, which is four times higher in malignant cells in comparison to healthy cells with no side effects. This finding is particularly pertinent to the targeting and treatment of cancer. These were also found to be less cytotoxic than gold nanoparticles [203].
Immunotherapy is a novel approach in the field of cancer treatment that garners antigen–antibody interactions. Interferon plays a great role in immunotherapy to treat cancer and act on target cells by binding with receptors that are present on target cells. Interferons produce antiproliferative effects (by inhibiting mitosis and growth factor, by activation of pro-apoptotic genes, and by promoting antiangiogenic activity) on cancer cells and also support the immune system to fight against cancer-causing agents [204]. A blinded prospective cohort study was performed where a 4-day regimen of topical calcipotriol and 5-FU was contrasted with a control regimen of Vaseline and 5-FU to treat Actinic keratosis (AK), which is a predecessor of squamous cell carcinoma (SCC). After 1, 2, and 3 years of trial, the incidents of SCC and BCC were accessed. It was observed from the study that the probability of developing SCC within three years of treatment is greatly reduced by a brief course of calcipotriol with 5-FU treatment on the face and scalp. This treatment is connected with the generation of strong T cell immunity and Trm production against AKs [205]. In a randomized trial using Nivolumab plus ipilimumab or nivolumab alone. It was suggested that patients with advanced melanoma who got nivolumab + ipilimumab or nivolumab alone had a higher percentage of sustained long-term survival rates and progression-free survival at 5 years than patients who were given ipilimumab alone, with no discernible decrease of quality of life in the nivolumab-containing regimens [206].
Ignacio et. al. researched the effect of intratumoral administration of cancer immunotherapeutics against tumor cells. The aim of the study was to evaluate the efficacy of the monothematic agent for reducing the tumor after intratumoral local administration as shown in Fig. 7 . The study results revealed that the direct tumoral administration of the iontophoretic entity causes increased efficacy or therapeutic index due to bypassed systemic exposure of the immunotherapeutic agent as well as drastically changes the toxicity profile of the immunotherapeutic agent [207].
Illustration of cell types, processes, immunotherapy, and their effect on the tumor after intratumoral administration. Adapted with permission from [207]
Checkpoint Inhibitors: These drugs block certain proteins that inhibit the immune response, allowing immune cells to recognize and attack cancer cells more effectively. Checkpoint inhibitors like PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitors are commonly used in skin cancer treatment.
Cytokine Therapy: Cytokines are signaling molecules that regulate the immune system. Interferons and interleukins are examples of cytokines used in skin cancer immunotherapy to enhance immune responses against cancer cells.
Cancer Vaccines: These vaccines stimulate the immune system to recognize and attack cancer cells. In skin cancer, therapeutic vaccines can target specific antigens expressed by cancer cells, boosting the immune response against them.
CAR-T Cell Therapy: Chimeric Antigen Receptor (CAR) T-cell therapy involves genetically modifying a patient's T cells to express receptors that target cancer-specific antigens. This personalized approach has shown promise in certain types of skin cancers.
PD-1/PD-L1 Inhibitors: Pembrolizumab and nivolumab are PD-1 inhibitors approved for advanced melanoma treatment. They target the interaction between PD-1 on T cells and PD-L1 on cancer cells, enabling immune cells to attack the cancer. Ongoing studies explore their combination with other therapies and their effectiveness in different stages of melanoma. (NCT02506153) compares the effectiveness of pembrolizumab versus high-dose recombinant interferon alfa-2B in treating patients with stage III-IV melanoma that has undergone surgical resection but are likely to recur or spread. High-dose recombinant interferon alfa-2B may aid in melanoma reduction or growth inhibition [208].
Anti-PD-1/PD-L1 therapy for skin cancer is revolutionizing management and results. The higher anti-PD-1/PD-L1 response rates in skin cancer relative to other solid tumor types are probably caused, at least in part, by a greater mutational burden. These drugs have 40–60% response rates when used as monotherapies, with many of those responses lasting a long time [209].
CTLA-4 Inhibitors: Ipilimumab is a CTLA-4 inhibitor used in advanced melanoma treatment. It enhances T cell activity by blocking CTLA-4, a protein that suppresses immune responses. Ongoing research investigates its use in combination with PD-1 inhibitors and its efficacy in preventing disease recurrence.
Ipilimumab boosts the immune system's reaction to cells of melanoma and tumors by inhibiting CTLA-4. The medication acts to stimulate T lymphocytes, allowing them to grow and destroy melanoma cells wherever they are found in the body [210]. This is an oncolytic virus therapy approved for advanced melanoma. It is injected into tumors that triggers immune responses against cancer cells. Studies focus on its application in combination with checkpoint inhibitors and in earlier stages of melanoma. It is used to treat melanoma skin cancer that is unresectable because it has spread to other parts of the skin, soft tissue, or lymph nodes. T-VEC functions as a targeted therapy to eliminate melanoma cells and reduce skin and lymph node lesions. However, it has not been demonstrated that T-VEC can reduce metastatic melanoma (melanoma that has spread to the brain, bone, liver, lungs, or other organs) or increase overall survival. T-VEC is a local treatment, which implies that in order to cure melanoma cells, it is given directly to the lesions. T-VEC's precise mechanism of action within the immune system remains not entirely understood. But it's suspected that along with killing cells directly, the virus may also trigger an immune reaction that fights melanoma by releasing antigens released from tumor cells, which are chemicals that trigger an immune response, and GM-CSF, a molecule that boosts the immune system [211, 212].
A phase I study (NCT03458117) was conducted for the evaluation of effectiveness, safety, and tolerability after repeated T-VEC injections in patients with non-melanoma skin cancer [211].
A phase III study (NCT02965716) aims to assess the effectiveness of talimogene laherparepvec (T-VEC) in combination with pembrolizumab (MK-3475) in treating patients who have progressed on prior anti-PD-1 or anti-PD-L1 therapy, either alone or in combination with other drugs other than talimogene laherparepvec (T-VEC) [213].
Cancer Vaccines: Therapeutic vaccines like the MAGE-A3 vaccine target specific antigens expressed by cancer cells. Ongoing trials are exploring their effectiveness in stimulating immune responses against melanoma. mRNA-based vaccines can also elicit cellular and humoral immune reactions [214]. They are intended to stimulate the immune system to fight an existing disease rather than avoid sickness [215]. A vaccine that boosts the synthesis of a protein essential to the skin's antioxidant network, according to research from the Oregon State University College of Pharmacy, may help people strengthen their resistance to skin cancer [216]. Clinical trials for an mRNA vaccine have shown potential in the treatment of stage 3 and stage 4 melanoma. The incidence of death and recurrence from stage 3 and stage 4 melanoma was reported to be 44% lower when the Moderna vaccination was used with immunotherapy treatments as opposed to immunotherapy alone [217, 218]. An I.M. or I.D./S.C. injection of the immunotherapeutic MAGE-A3 was used in an open-label randomized single-institution pilot study (NCT01425749) to assess the safety and immunologic response. It was found that both immunization routes were well tolerated and free of grade 3 adverse treatment-related events [219]. Another study (NCT00002952) aims at determining the safety and maximum tolerable dose level of the MAGE-3 or Melan-A (human tumor antigen genes) peptide-pulsed autologous peripheral blood mononuclear cell and interleukin-12 vaccination should be determined. It also aimed to ascertain whether the procedure successfully immunizes the patient and to evaluate the tumor’s reaction to the vaccination [220].
BRAF/MEK Inhibitors with Immunotherapy: In melanoma cases with BRAF mutations, targeted therapy with BRAF and MEK inhibitors is combined with immunotherapy to maximize treatment response. Clinical trials are assessing the efficacy and safety of these combinations. When used before or simultaneously with immune checkpoint inhibitors, BRAF/MEK inhibitors at least momentarily change several immunosuppressive tumor microenvironment characteristics, which could possibly increase immunotherapy sensitivity [214]. The phase III trial IMspire150, which added atezolizumab (an anti-programmed death ligand 1 [PD-L1] drug) to cobimetinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor), produced encouraging findings for the first time in 2020. Despite the fact that response rates were comparable between the two arms, this immune/targeted triplet was observed to significantly lengthen the duration of response (DoR) and progression-free survival (PFS) [221].
A phase III trial (NCT01909453) compares the effectiveness and safety of LGX818 with MEK162 to vemurafenib and LGX818 monotherapy in patients with locally progressed, unresectable, or metastatic melanoma with the BRAF V600 mutation in two parts. There will be 900 patients randomized in total (64).
New Checkpoint Inhibitors: Beyond PD-1 and CTLA-4 inhibitors, researchers are developing novel checkpoint inhibitors targeting other immune checkpoints. These inhibitors are being studied in clinical trials for their potential in skin cancer treatment. It is imperative to research novel avenues targeting immune checkpoint receptor proteins because of the treatment resistance, poor response, or considerable increase in toxicity of antibody medicines targeting PD-1/PD-L1 or CTLA-4 that have previously been found [222, 223]. LAG-3, also known as CD223 or FDC protein, belongs to a new class of immunological checkpoint receptors [224]. According to studies, blocking or inhibiting LAG-3 can restore the cytotoxic activity of T cells, lessen the function of regulating T cells in suppressing immune responses, and increase the effect of T cells in destroying tumors. Beyond PD-1/PD-L1 and CTLA-4, LAG-3 has emerged as a novel tumor immunotherapy target as an indication of tumor prognosis [225, 226]. A phase II clinical trial (NCT03666325) aims to study the fighting of primary and secondary resistance with Immunotherapy after EGFR inhibitors in locally advanced or metastatic squamous cell carcinoma [227].
Personalized Immunotherapy: It is a type of highly individualized cancer therapy that uses the patient's immune system to battle tumor cells. For patients whose cancers do not respond to conventional therapy, the discovery of uncommon anti-tumor lymphocytes that can infiltrate and aid in the destruction of metastatic solid epithelial tumors could promote the development and efficacy of personalized cancer immunotherapies [228]. CAR-T cell therapy is being explored in certain skin cancers. Researchers are identifying specific antigens and designing CAR-T cells to target them, with ongoing studies to assess their effectiveness and safety.
A phase I trial (NCT03893019) using CD20 CAR-transduced T cells to treat melanoma will be the first one in Europe. The trial's justification is based on the discovery that CD20 is expressed by melanoma cancer cells and that killing CD20+ cells in preclinical models produces potent anticancer effects [229]. For the treatment of patients with stage IIIC or IV melanoma, this phase I trial (NCT04119024) investigates the adverse effects and optimal dose of modified immune cells (IL13Ralpha2 CAR T cells) [230].
Combination Therapies: Many ongoing trials focus on combining different immunotherapies, targeted therapies, or conventional treatments to enhance response rates, reduce side effects, and improve overall survival in skin cancer patients. The combination of anti-cancer medications improves efficacy in comparison to monotherapy because it targets important pathways in a manner that is typically additive or synergistic. This method may decrease the occurrence of drug resistance while also having therapeutic anti-cancer effects, such as lowering the growth of the tumour and metastatic potential, stopping mitotically active cells, lowering cancer stem cell populations, and causing apoptosis [231].
A Randomized, Double-blind, Placebo-controlled, Phase III Study (NCT02967692) is being conducted to evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma (63). A clinical trial with identifier NCT02224781 titled “Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients with Stage III-IV BRAFV600 Melanoma” aims to determine whether the following will significantly enhance 2-year overall survival (OS) in patients with stage III or stage IV BRAFV600 mutant melanoma that is not amenable to surgery (60).
It is generally a dependent treatment and normally used for cancers that were present in closely associated lymph nodes and distant sites lymph nodes or any other organs located on distant areas, hence could be preferred for stages 1, 2, 3, and 4 of melanoma cancer. In this technique, drugs are used which were delivered on the target i.e., mutated genes and molecules present in melanoma cells stop the growth as well as affected the action of tumorous cells and also stop the proliferation of melanoma cells.
The medications used in targeted therapy arrest the proliferation of melanoma that constituted mutated serine/threonine-protein kinase B-Raf (BRAF), Mitogen-activated protein kinase (MEK), or tyrosine-protein kinase Kit (C-KIT) genes. Targeted therapy is only confined to these mutated genes, but not all melanoma cells do not possess these genes. Hence targeted therapy is not applicable to all types of cancer [232].
In a chemical peel, medical practitioners have to apply trichloroacetic acid (TCA) on the cancerous lesions directly, which results in the removal of the top layer of the skin. It is mainly used for precancerous skin lesions. The three types of chemical peels are; (i) Superficial peel – this kind of peel normally removes the top layer of the skin, (ii) Medium peel – this kind of peel is able to remove middle layers of skin, (iii) Deep peel – this kind of peels are able to penetrate the skin deeper and remove the deeper most layer of the skin.
Chemical peel treatment can be less costly and less complicated as compared to other treatments. Chemical peel treatment can make the skin appear red and the patch can stay for a month or a couple of months discoloration of the skin may be possible as the skin can become darker or lighter [233]. One review summarized the available data on the effects of chemical peels on UV- induced cancer of the skin. For the analysis, a total of 42 articles including in-vitro and in-vivo human and animal models were used. The information mostly concerned lab animals. The results indicate that chemical peeling may have clinical applications for the prevention of skin cancer in addition to its effectiveness in removing visible actinic keratoses. There is currently no proof that human skin exposure to chemical peels causes systemic harm [233].
Radiotherapy is a successful and adaptable non-surgical (or medicinal) approach for tissue preservation. Radiotherapy is a fantastic alternative for people in whom excision may not be possible (medically or technically inoperable) or may be viewed as less optimal (e.g., cosmetic outcome). Adjuvant radiation after surgery can reduce the incidence of recurrence and related morbidity in individuals with unfavorable histology. When surgery is not a possibility, elderly and co-morbid individuals with low functional outcomes can profit from relatively brief hypo-fractionated radiotherapy [234]. In radiation therapy, the radiation is just focused on the outer surface of the skin on the tumorous area. The low energy x-ray (superficial radiation therapy) or electrons (electron beam radiation) is used for radiotherapy and it doesn’t penetrate deeper into the skin [235]. Radiotherapy is one of the prevailing kinds of treatment done by skin cancer patients. In the US approximately 50% patients of with skin cancer have an indication of performing radiotherapy at least once in the whole course of their disease. But most of the patients can’t receive the treatment due to a shortage of important resources including equipment as well as personnel for handling the instrumentation or the expertise persons who can do the whole treatment [236]. A phase II study was carried out for evaluating how older individuals with early-stage NMSC respond to accelerated radiation therapy (RT). Out of 31 study subjects, 30 showed complete responses. Concluding that > 90% of people had local control of disease which is considered to be a good or excellent result [237]. The results from a meta-analysis consisting of 344 articles published between the years 1985- 2016 were analyzed and it was concluded that for more than 80% of patients with cutaneous BCCs/SCCs, hypo fractionated RT has a positive cosmetic outcome [238]. Different approaches for tackling/ Management of skin cancer are well illustrated in Fig. 8 .
Representation of different approaches for the management of skin cancer
Several treatment strategies have been designed to treat the never-ending rate of skin carcinoma. A void in the therapy regimen should be filled to facilitate cellular inhibition and apoptosis. The section below discusses the scope of the dermal therapeutic approach against skin cancer.
Dermal drug delivery represents a broad term used to address the administration of dosage forms via transdermal (across) or topical (into) the skin [239]. In addition to oral, hypodermic, and intravenous injections, etc., the dermal drug administration technique has recently emerged as a crucial therapeutic strategy. The dermal approaches provide a number of advantages over competing ones [240]. In comparison to injections, it is painless, and because it uses needle-free technology, there is essentially no chance of disease transmission through the reuse of needles. This can help to reduce medical waste, which is a common source of medical malpractice, particularly in developing nations. Once more, the transcutaneous method can simply get around the drawbacks of the oral route. It can prevent gastrointestinal breakdown as well as first-pass or pre-systemic metabolism, in which the drug's dosage is drastically decreased before it even reaches systemic circulation. Consequently, it can increase the active pharmaceutical ingredients' (APIs) bioavailability. The non-invasive nature of the transdermal patches makes it a self-administered technology with better patient compliance, and they can deliver medications in a much more well-controlled manner over an extended period of time [240, 241]. Topical treatment may be more effective in some circumstances, especially in cases where the patient refuses surgical assistance or surgery is not an option. As a matter of fact, dermal or transdermal therapy is frequently advised to individuals who have several clinical and subclinical lesions spread across a significant anatomical area or field cancerization. In addition, topical therapy may result in lower patient toxicity than systemic therapy and higher medication concentrations at the tumor site [242].
The current dermal therapy for skin cancer includes 5- Fluorouracil, retinoids, Ingenol mebutate (IM), IMQ. Some of the phytopharmaceuticals used as dermal therapy include sinecatechins, Patidegib, BIL-010t, Gingerol, Betulinic acid, Epigallocatechin-3-gallate, Colchicine, resveratrol, quercetin, and curcumin.
A 5% cream or solution of 5-FU is a common topical agent used against superficial Basal Cell Carcinoma (sBCC). 5-FU has been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a therapeutic of sBCC along a dosage regimen of two times a day for two to four weeks. The pyrimidine analog 5-FU is an antineoplastic antimetabolite, and through 5,10-methylene tetrahydrofolate which is a co-factor, it shows binding to thymidylate synthase. As a result, thymidine synthesis is inhibited, DNA replication is compromised, and apoptosis is subsequently induced [243].
In a prospective, single-arm study, 5-FU cream (5%) was used on 29 patients with a total of 31 sBCC lesions on the trunk or limbs as confirmed by histology. The treatment was done two times a day for a period of 12 weeks. The histological analysis showed that 28 lesions (or 90%) out of the 31 were cured [242].
Patients with sBCC in a randomized controlled study were given 5% of 5-FU two times a day for 4 weeks, MAL-PDT twice a week apart, and 5% cream of imiquimod once a day for six weeks. Five- year follow- up was done on the patients. At 1 year the estimated success of treatment was 80.1% with 5% 5-FU, 72.8% for MAL-PDT, and, 83.4% on using imiquimod which has proved the superiority of imiquimod to MAL-PDT in treating sBCC while topical 5-FU was not inferior. Adnexal expansion and tumor thickness in sBCC did not seem to indicate treatment failure. The likelihood of being tumor-free five years after treatment with 5% 5-FU was 70.0%, with MAL-PDT was 62.7% and 80.5% for imiquimod. Thus, proving the superiority of 5% 5-FU over MAL-PDT and that of imiquimod over both 5-FU and MAL-PDT [167].
The consideration of 5-FU as a treatment option for sBCC is possible, however, it should only be used on people who are unable to have surgery and have small lesions in low-risk sites. Additionally, long-term follow-up must be maintained. Sahu Prashant et. al. worked on the pH-responsive biodegradable chitosan nanogels incorporated with 0.1% and 0.2% 5-FU, and the developed formulation was applied topically on the Swiss albino male mice bearing skin cancer and compared with the control. The study showed promising results in terms of reducing tumor size and efficacy of the formulation. As shown in Fig. 9 , the Group G1 (Control), G2 (Toxic group), G3 (treatment with conventional 5-FU formulation), G4 (treatment with 1% 5-FU loaded chitosan nanogel), and G5 (treatment with 2% 5-FU loaded chitosan nanogel). The decreasing order of efficacy found after conducting the study on tumor-bearing mice was G5 > G4 > G3 > G2. The graph represented in Fig. 9 also shows the tumor burden in G5 was minimum compared with the remaining groups [244].
Physical methods employed for enhancing the penetration ability of the drug
IMQ is a synthetic compound of low- molecular weight. It belongs to the family of imidazoquinolinone. A high range of tumor necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha), and other interleukins (IL-6, IL-8, IL-10, and others) are determined by IMQ's binding to Toll-like receptor (TLR-7) and -8. It is possible that IMQ could be utilized for individuals having skin cancers, particularly in smaller tumors at insubstantial- risk areas, those not convenient for alternate treatments since it can also cause cell apoptosis [245]. 5% cream of IMQ is used off- label for nBCC. However, it is an approved drug used against sBCC [242].
A randomized trial was carried out to assess the effectiveness of topical IMQ and ascorbic acid for treating BCC. 25 patients with BCC confirmed by 29 biopsies were randomly allocated to be given topical imiquimod, or topical ascorbic acid solution two times a day for 8 weeks. In the ascorbic acid group, 13/15 (86.7%) of the lesions had completely disappeared after 8 weeks, but with IMQ the lesions disappeared only in 8/14 (57.1%) cases. The superiority of topical ascorbic acid over topical imiquimod in the treatment of low-risk nodular and surficial lesions was found at 8 weeks and by 12 weeks it was found to be non-inferior. Additionally, in comparison ascorbic acid was linked to fewer side effects than IMQ. At the 30-month follow-up, persistent hypopigmentation was found in 70% of individuals belonging to the IMQ category, compared to 0% in the ascorbate category [246].
One of the studies concerning therapy with topical IMQ 5% has demonstrated a higher rate of success when compared to PDT and 5-FU. Although there does not appear to be a correlation between the thickness of the tumor and the rate of success for the three aforementioned treatments [245].
A systematic review was done by Huang and colleagues on the use of topical IMQ as a treatment option for nBCC including its safety and efficacy. The treatment regimen varied from once daily twice a week to two times daily 7 days a week. It was concluded that histological and clinical clearance rates for nBCC treated with imiquimod exceeded 70%, with a recurrence incidence of 1.80%. Although IMQ has lower clearance rates than surgery, it can be used to treat nBCC in patients who are unwilling or unable to undergo surgical intervention [247].
According to case report data, IMQ may be utilized in some situations as a treatment prior to surgical excision of high-risk BCC or as an adjuvant therapy for partially removed tumors [248]. Topical IMQ has the benefits of being self-applied, being a non-scarring therapy, being less costly, and being less painful. Additionally, it can be utilized as a substitute for surgery for lesions that include sensitive regions or huge areas that are resistant to surgery [242]. Franca, et al. developed a polymeric nanoparticle containing Imiquimod and the efficacy of these formulations was compared with the marketed Imiquimod formulation, Placebo as well as Tumor control. The efficacy of each formulation was determined on the tumor-bearing rats based on the reduction of no. of papilloma in each group as shown in Fig. 10 . The study results revealed that the Imiquimod loaded polymeric nanoparticles showed greater efficacy against tumors followed by the marketed Imiquimod formulation and placebo showing the enhanced effectiveness of the Nano formulation approach over the conventional formulation of Imiquimod [249].
SEM image of Me300 melanoma cells in which A) represents cells not exposed to iron oxide nanoparticles while B and C) represent treatment groups exposed to amino ultra-small superparamagnetic iron oxide nanoparticles [250], (D) influence of @BSA-RF@RGD on AuNRs uptake [251], (E) FESEM and TEM images of ZnO nanoparticles in which Low magnification FESEM image, (F) high-magnification FESEM image, (G) Low magnification TEM image of ZnO, and (H) high-magnification TEM image of ZnO showing distance between lattice fringes around 0.265 nm [252], (I and J) TEM and FESEM image of cerium oxide nanoparticles respectively. Adapted with permission from [253]
Retinoids were discovered in 1913 and are defined to be natural or synthetic derivatives of vitamin A. Basal cell carcinomas (BBCs) have responded well to treatment with retinoic acid derivatives. Retinoids exert their chemo-preventive effects by arresting the growth of tumor cells, apoptosis, altering the immune response or keratinocyte differentiation, or by a combination of these actions. Retinoids interact intracellularly with cytosolic proteins as well as two families of retinoic acid receptors (RARs), nuclear receptors, and retinoid X receptors (RXRs). This activates downstream targets’ transcription that contains retinoic X response elements (RXREs) or retinoic acid (RAREs). Skin malignancies have been treated with isotretinoin (also known as 13-cis-retinoic acid), tretinoin (also known as all-trans retinoic acid), tazarotene, and adapalene. However, they are all in use experimentally off- label, as none of them have been approved. In particular, a clinical investigation investigated how to treat sBCC or nBCC, for this once-daily application of 0.1% tazarotene gel for up to 8 months was carried out. It was observed that 5 of 17 nBCC cases and 11 of 13 sBCC cases showed elimination of lesions. The development of alternate forms of therapy to BCC lowered the use of topical retinoids.
A randomized, open, controlled trial comparing tretinoin 0.05% cream with low-dose oral isotretinoin was conducted for the purpose of treating field cancerization. The results indicated that retinoids are efficient and secure for field cancerization because there was no difference in the outcomes between the two treatments. Retinoids are a suitable option to intercalate with traditional field cancerization therapies (IM and IMQ) which are used for short time periods. However, retinoids can be taken constantly [254].
Tazarotene, a retinoic acid derivative was successfully used in one of the clinical study to treat BBCs. Another retinoid called Fenretinide is thought to be among the most optimistic. Skin tumor cells as well as other cancer cells are cytotoxic to the substance. N-(4-hydroxyphenyl) retinamide (4-HPR) impacts tumors by generating ROS, boosting the formation of dihydroceramide, encouraging angiogenesis inhibition, and enhancing Natural killer cells (NK) cell activity [255].
IM is one of the extracted substances from Euphorbia peplus plant sap. IM is marketed by LEO Pharma with the brand name Picato and is an activator of protein kinase C. IM causes cellular cytotoxicity and prevents recurrence by promoting the development of anti-tumor antibodies and proinflammatory cytokines [245]. It is approved for treatment against actinic keratoses but is used off-label for SCC and BCC [256].
Treatment with IM gel has been demonstrated to be an effective therapy for both non-pigmented and pigmented superficial BCC, with no significant adverse events. Histology and dermoscopy techniques were used to observe these outcomes. Only the highest concentration (0.05%) administered over a period of days was significantly superior to the vehicle when used to treat superficial BCC, according to a phase II trial. More studies are required as currently indicated therapy for BCC is off-label [257].
According to Erlendsson et al., repeated IM field-directed treatments prevent hairless mice from developing UV-related SCC. Additionally, the scientists discovered a correlation between higher local skin responses, such as erythema, flaking, crusting, vesiculation, swelling, and ulceration, and better clinical results. At the moment, it is used off-label to treat SCC [258].
M. R. Fuente and colleagues performed a study concerning topical IM 0.05% gel in BCC, triggering the inflammatory response and its characterization. 16 patients with distinct BCC subtypes were prospectively assessed and treated with IM gel 0.05% once daily for two days in a row under occlusion. Patients were randomly assigned into two arms, patients in one of the arms received biopsies between the 3 rd and 10 th day following the start of the treatment (referred to as the "early immune response") and another arm received biopsies at the thirty-day mark (referred to as the "late immune response"). Complete remission in 10 BCCs was found after 2 years of follow- up. It was concluded that IM gel causes a brief immuno-inflammatory response as well as a significant necrotic reaction [259].
Another study described the example of the 100-year-old woman with a massive nBCC (nodular BCC) of the face. IM 0.015% gel was used for three days in a row, once a day. Seven cycles of this dosage regimen were administered over the course of 11 months, and the tumor was completely cured. Mild localized cutaneous responses that were well tolerated were noted. IM gel may be used to treat some cases of nBCC; however, the ideal medication concentration and dosage schedule have not yet been established. Below listed Table Table2 2 represents the FDA-approved drugs for the management of skin cancer.
List of drugs approved by FDA for skin cancer treatment
Cancer has many potential ways to worsen since it can develop as a result of mutations in several pathways that are present in our bodies. Due to this characteristic, treating cancer patients with monotherapy alone becomes challenging and runs the risk of not completely curing the disease. Therefore, the need was felt for combinatorial therapy, which includes the simultaneous use of two or more methods or drugs for the treatment of a disease. A combination of two or more drugs or methods would target multiple pathways simultaneously and would help in the better treatment of cancer. This has also yielded a higher success rate as compared to monotherapy. Combinatorial treatment involves the complimentary pairing of two separate therapies, such as the pairing of radiotherapy with immunotherapy or the pairing of medications that can target several cancer-formation pathways. Along with complimenting each other, the combination also leads to reduced drug resistance which is generally seen with monotherapy [260, 261].
Multidisciplinary involvement in the treatment of local, regional, or distant metastatic cSCC is necessary. When lymph nodes are involved, NCCN (National Comprehensive Cancer Network) advises excision lymphadenectomy or parotidectomy. Depending on the results of the margin assessment or if extracapsular lymph node expansion is observed, adjuvant chemoradiation may be considered [262].
In one of the studies (NCT03057613) concerning SCC, Pembrolizumab was added along with postoperative radiotherapy. The study showed 94.4% progression-free survival and no dose-related toxicity. Some minor toxicities like anemia, rash, fever, edema, etc., were found in 5.56% of the participants [263]. A phase 3 trial (NCT03833167) is underway, recruiting participants with CSCC (advanced but not metastasized), using pembrolizumab against placebo following radiation and surgery (MK-3475–630/KEYNOTE-630). The findings of a phase II trial (NCT01979211) named “Post-operative Radiation with Cetuximab for Locally Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck” showed 91.1% local–regional control, 70.8% disease-free survival, 56.1% overall survival and a 37.5% of participants faced all-cause mortality [264].
Singh et. al. formulated liposomal gold nanoparticles encapsulating curcumin and used it as an adjuvant with photothermal treatment. When compared to free curcumin, Curcumin encapsulated gold nanoparticles considerably improved uptake. Following laser irradiation, the group treated with curcumin gold nanoparticles showed enhanced cytotoxicity to cancer cells because of the presence of curcumin. The study suggests that for the treatment of melanoma, curcumin can be used as an adjuvant along with PTT [265]. Moghaddam et. al. formulated PEG- curcumin- gold nanoparticle (PEG- cur- Au NP) and used it as a near-infrared photothermal agent, it was found that when this is used in combination with 808-nm diode laser irradiation, a sizeable reduction in the volume of the tumor was seen in- vivo, with no adverse effects on the animal's well-being [266].
Cheng et. al. designed a Titanium-dioxide-nanoparticle–gold-nanocluster–graphene (TAG) heterogeneous for efficient utilization of sunlight which resembles melanoma skin cancer PDT, which would decrease or make the pain less severe as compared to PDT. TAG nanocomposite when used on mouse B16F1 melanoma cells has shown significant toxicological reactions when exposed to simulated sunlight. These toxicological reactions include glutathione depletion, intracellular reactive oxygen species generation, mitochondrial dysfunctions, and expression of heme oxygenase-1. Furthermore, in mice bearing B16F1 tumor xenografts, intratumoral or intravenous treatment with TAG nanocomposites can effectively suppress cancer growth and result in severe clinical tumor tissue alterations [267].
Following illumination (720 J/cm2; 650 nm filter) using or excluding a gel of kojic acid, a transethosome encapsulating ferrous chlorophyllin (Fe-CHL), a lipid-based NP, caused a progressive reduction in the size of the tumor in a melanoma mouse model, which totally regressed under one month [268]. Chlorin-e6 also called meso-tetraphenyl morphine – Mn (III) chloride, which is a generation- three photosensitizer, showed effective internalization within malignant melanoma cells after being encapsulated in liquid crystalline nano dispersions (LCNs), and they showed notable photodynamic effects after being exposed to radiation as compared to free photosensitizer (PS) [269]. Following exposure to radiation (0.5, 1.0, and 2.0 J/cm2; 670 nm filter), aluminum chloride phthalocyanine loaded SLN showed a decrease of 3.2-fold in the viability of the cell line (B16F10) [270].
Photodynamic therapy (PDT) in combination with photothermal therapy (PTT) is now showing promise in cancer therapy, overcoming PDT's intrinsic limitations. Complete cell/tumor eradication has been seen in one as well as other in- vivo along with in- vitro, recommended that the combined PDT/PPTT action caused by AuNRs/MoS2-ICG is significantly more effective than either one of synergistic PPTT or PDT alone. Remarkably, the two plasmonic nano agents producing synergistic PPTT have higher antitumor activity in- vivo as compared to PDT or PTT alone. When used in conjunction, the simultaneous PDT/synergistic PPTT approach efficiently shortens the duration of the therapy, has a high therapeutic index, and provides a safe treatment alternative as a cancer therapeutic [271].
Gefitinib was inspected in phase II single-arm analysis (NCT00126555) in persons suffering from CSCC who were contenders for curative therapy, such as radiation or surgery. 13 patients (35%) had a stable illness at 8 weeks, with an overall response rate of 16%. The median response and progression-free survival times, respectively, were 31.4 months and 3.8 months. A modest amount of efficacy was seen by gefitinib in incurable CSCC, and its adverse event profile was favorable [123].
In a multicenter Randomized Control Trial, the use of diclofenac gel in addition to cryosurgery showed to be superior to cryosurgery alone. Photodynamic therapy has also demonstrated efficacy against nonmelanoma skin cancer as well as premalignant lesions, either alone or in conjunction with topical immunomodulators [204]. Wang et al. reported that light-responsive Doxorubicin (DOX) -loaded nanocapsules showed considerable anticancer action in vivo as well as in vitro. The study found that succeeding with receiving pulsed microwave radiation exposure, the nanocapsules consumed energy to create a significant thermoacoustic shockwave that concurrently split fragments into ammonia as well as carbon dioxide, resulting in the creating the partial vacuum condition and eventually causing cellular destruction. The thermoacoustic shockwave as well as gas bursting emanate in the production of a significant number of destructive cells. Then, to begin cell death, DOX was released into the nucleus from the cytosol [272]. In one study, imiquimod (R837) loaded gold nanorods (GNR) coated with cetyltrimethylammonium bromide (CTAB) and adorned using polyethylene glycol (PEG), bovine serum albumin (BSA) was used as an immunoadjuvant. In mice with metastatic melanoma, the produced nano complexes subjected to near-infrared (NIR) radiation can provoke potent immune responses and efficiently destroy tumors. Melanoma and other malignant tumors may potentially be successfully treated with the nano complex-based PTT in conjunction herewith immunotherapy [273].
The delivery of medications to an area of interest using iontophoretic devices has been modified for the treatment of cancer. Iontophoresis is a drug delivery technique that involves applying a small electric current all around a drug reservoir to enhance drug transfer into the surrounding tissue [274]. Jose et al. studied the treatment of skin cancer using topical iontophoretic liposomal co-delivery of STAT3 siRNA and curcumin. Cationic liposomes complexed with STAT3 siRNA were used to encapsulate the curcumin. In an excised porcine skin model, iontophoresis applied topically was used to examine the penetration of nano complexes through the skin. The outcomes demonstrated that cells preferentially absorbed the curcumin-loaded liposome-siRNA combination through clathrin-mediated endocytosis. In comparison to free STAT3 siRNA and neat curcumin treatment, liposomal delivery of curcumin along with STAT3 siRNA significantly increased inhibition of the growth of cancer cells and apoptotic activities. Additionally, topical iontophoresis application improved the skin's ability to allow viable epidermis to penetrate nano complex [274–276]. Another study showed an enhanced skin penetration of the drug by iontophoresis. An EGFR-targeted 5-FU-loaded immunoliposome was developed. The study exhibited that penetration through viable epidermis doubled for 5-FU by iontophoresis of immunoliposomes in comparison to identical therapy using control liposomes. The therapeutic effectiveness was confirmed by the results in a mouse skin cancer model, which showed a decrease in cellular proliferation and tumor volume [277].
Targeted modulation and site-specific administration of therapeutic drugs are made possible by the spatiotemporally programmable application of ultrasound, either with or without ultrasound contrast agents [278]. Through the activation of sonosensitizers by low-intensity ultrasound, sonodynamic therapy (SDT) has turned out to be a viable treatment alternative for the management of cancer. Docetaxel is loaded onto a redox/enzyme/ultrasound responsive chondroitin sulfate-chlorin e6-lipoic acid nanoplatforms, integrating chemotherapy and SDT, for the prevention of growth of melanoma as well as metastasis. Chemo SDT along with the prevention of tumor development and metastasis by lowering the expression of metastatic proteins, but also triggered an immune response by releasing antigens related to the tumor. The nanoplatforms demonstrated good blood compatibility and in-vivo stability, proving them to be efficacious and safe in drug delivery [279].
Curcumin and Topotecan were evolved by Prasad and Banerjee co-encapsulating nanocapsules and microbubble nanoconjugates for spatiotemporal delivery in melanoma. When ultrasound was used along with this developed formulation the effect in terms of reduced tumor growth was found to be 3.5 and 14.8 times more as compared to when ultrasound was not used and when only a physical mixture of drugs was used, respectively [280]. Below listed Table Table3 3 elaborates on the list of ongoing clinical trials on physicochemical combination therapies for the management of skin cancer. Figure 11 represents different physical methods of penetration enhancement for the drug.
Elaborates the list of ongoing clinical trials on physicochemical combination therapies for the management of skin cancer
