Irradiation of the skin causes tissue damage and inflammatory cell recruitment by damaging epidermal basal cells, endothelial cells, vascular components and reducing the number of Langerhans cells (42). Radiation dermatitis is a particularly common side reaction to radiotherapy for head and neck carcinoma. Most patients experience mild to moderate degrees of skin lesions (such as grades I and II) but up to 25% develop severe reactions. In severe radiation dermatitis (grades III or IV), the epidermis is infiltrated with neutrophils and there are high rates of apoptosis in the deeper layers (43). The standard administration of radiation involves successive doses and it frequently prevents tissue healing due to cellular repopulation, even if the patient takes a few days to break during cures of daily fractionated therapy, thereby compromising the result (44). The general management of radiation dermatitis includes washing once or twice a day with pH-5 soap, moisturizing shaving to prevent folliculitis, debridement and checking for systemic inflammation (45). Is it highly recommended to use aloe vera and to avoid exposure to sunlight, scratching and local trauma. To prevent severe skin toxicities, patients and physicians must look for early signs of radiation dermatitis (46).

The development of vaccines is currently the most widespread method to prevent infections with different germs or the development of cancer cells (47). Head and neck squamous cell carcinoma, including cutaneous locations, is caused by both external conditions and genetic mutations. Cancer vaccines may be of two types, prophylactic and therapeutic (48). Therapeutic vaccines use the host's immune system to recognize and eliminate cancer cells (49). It acts in the opposite direction of tumor invasion mechanisms (50), targets antigens associated with tumors, and induces a widespread mediated immune response (51). Current research includes modified virus tumor vaccines, DNA, proteins, peptide-based vaccines and combined strategies, all demonstrating encouraging results (52).

Peptide-based vaccines. The purpose of peptide-based vaccines is to stimulate the body's immune system. After the administration of the vaccine, the antigens are taken up and processed by the antigen-presenting cells (53). The antigen is then delivered via the T-cell receptor (TCR)/major histocompatibility complex (MHC) complex to CD8+ T-cells (54). These may differentiate into cytotoxic T-cells that are capable of directly killing cancer cells. Compared to classic vaccines, the peptide-based ones have no mammal cytotoxicity, are less likely to induce allergies or autoimmune responses, are relatively simple to produce and are cost-effective, allowing the expansion of production depending on the need (14). The addition of lipids, carbohydrates and phosphates is allowed in order to improve stability and immunogenicity (55). Peptide purity may be evaluated by techniques such as mass spectrometry. In addition, peptide stability may be demonstrated by standard physicochemical characterization (56). They contain several epitopes and may be designed to target single or multiple pathogens in different phases of the cell life cycle (57). Genetic recombination has not been associated with any documented risks (58). The main issue with using peptide-based vaccines remains poor immunogenicity and the need for an administration system or adjuvants such as TCR ligands, cytokines or co-stimulatory molecules to obtain the intended effect (59). Another limitation of vaccines is the restriction of MHC molecules. They must match the patient's human leukocyte antigen (HLA) (60). In individuals with different MHC class, I molecules, a specific trigger may not induce cell-mediated immunity. In addition, due to HLA polymorphisms, it is difficult to create a universal, effective vaccine for the entire human population. The solution to this problem may be the development of a long peptide containing multiple antigenic epitopes (61). For instance, patients with positive HLA-A24 who suffer from oral cancer may safely use the Survivin-2B peptide vaccination in order to achieve tumor regression (62). Survivin-2B is a novel member of the inhibitor of apoptosis protein family and may be found in most malignancies but is rarely expressed in normal adult tissue. This apoptosis inhibitor is the only one that is expressed in the G₂ and M phases of the cell cycle (63). Its oncogenic potential lies in its capacity to overcome the G₂-M checkpoint for mitotic progression (64). Survivin-2B80-88-specific cytotoxic T-lymphocytes were induced from peripheral blood mononuclear cells after stimulating the peptide in vitro. The vaccine may be injected subcutaneously or intratumorally with important therapeutic potential and no adverse events (65).

DNA and RNA vaccines. Nucleic acid-derived vaccines may be synthesized faster than peptide-based ones, which is one of their advantages. DNA vaccines are used with molecules such as IL-2 and macrophages or granulocytes, which are relatively stable and able to activate CD4+ and CD8+ T-cells (66). Furthermore, plasmid DNA may also activate the inborn immune system by recognizing the double-stranded DNA structure. To be effective, DNA vaccines require to penetrate the cell membrane and the nuclear membrane (67). RNA vaccines do not need to penetrate the nuclear membrane but are less stable compared to DNA vaccines. In a previous study, RNA epitopes were given as liposomal complexes. The complex was successfully taken up by dendritic cells, producing an immediate antigen-specific T-cell response (68). Currently, these vaccines are in the experimental phase and are personalized, but they may become the standard for head and neck SCC immunotherapy (69).

MiRNAs are single-stranded RNA molecules with a length of 21-23 nucleotides that control the expression of >50% of human genes. Each miRNA molecule is able to recognize numerous mRNA transcripts and regulate a great number of genes downstream (70). The activity of miRNA involves modifications of the cell cycle, cellular differentiation, proliferation, survival, motility, apoptosis and morphogenesis, which are all involved in the carcinogenesis of head and neck carcinoma (71). Metabolic reprogramming is an important indication of cancer, and as a highly dynamic process, it facilitates the transformation of a normal cell into a malignant cell (72). Aerobic glycolysis is an altered metabolic pathway frequently observed in cancer cells. The mechanism changes the role of cell energy, making it less efficient but supporting invasion, migration and drug resistance. For this substantial amount of energy, cancer cells require a higher glucose intake (73). The glucose transporter (GLUT) protein family has 14 members, but only GLUT1 and GLUT3 are aberrantly expressed in carcinomas of the head and neck (74). MiR-218 is a tumor-suppressor mRNA that downregulates the proliferation, invasion and metastatic potential of numerous types of cancer cell. Inhibition of miR-218 by activating GLUT1 expression increases proliferation and glucose uptake (75). Related to miR-218, miR-340 regulates GLUT1 expression by increasing glucose absorption and lactate secretion. Inhibition of miR-340 activates GLUT1 and promotes proliferation and colony formation with high glucose uptake. Another mRNA with an oncogenic role in head and neck SCC is miR-10a, which acts like an upstream regulator of GLUT1(76). The metabolic processes regulated by miR-340 in head and neck SCC are presented in Fig. 2.

The Cancer Genome Atlas data confirmed the upregulation of another mRNA in head and neck SCC, miR-31-5p. The overexpression of miR-31-5p increases free fatty acids aggregation and lipid droplet formation by targeting acyl-CoA oxidase 1, enhancing prostaglandin E2(77). MiR-31-5p promotes migration and invasion of cancer cells (78).

As head and neck SCC is a group of different cancers, various anatomical areas may serve as a starting point with diverse characteristics and outcomes. Currently, studies are devoted to the identification of site-specific miRNA signatures for every subtype of SCC (79).

Tumor progression and drug resistance are strongly associated with defects in apoptosis signaling (80). Dysregulation of apoptosis chaotically prolongs cancer cell life, resulting in gene mutations (81). The Bcl-2 family of proteins is relevant in the apoptosis signaling process through their anti- and pro-apoptotic members, which may interfere with one another's functions while heterodimerizing and controlling the death signaling pathway. Members of the Bcl-2 family are frequently expressed in head and neck SCC, with various locations, including on the skin, where they have a key role in tumor initiation and evolution (63). Since overexpression of Bcl-2, Bcl-X_L or survivin is associated with Cisplatin and Etoposide chemoresistance in head and neck carcinomas, biological research indicates that antisense oligonucleotides may be used as a competitor in favor of tumor cell death (82). Antisense oligonucleotides have therapeutic potential by inhibiting Bcl-2 proteins and blocking tumor cell progression. In addition, decreasing Bc-X_L expression induces apoptosis in gastric cancer cells (83). In vitro experiments demonstrate an increased apoptosis rate and high drug sensitivity when antisense oligonucleotides are used against survivin expression (84).

Several studies have been performed with different strategies regarding the treatment of head and neck carcinoma. Whether combining drugs with radiation or just using immunotherapy, recent trials indicated positive results regarding not only the regression of the tumors, control of metastatic rates and recurrent behavior, but also severe adverse events (85). The trials looked at the effects of specific drugs such as HF-10, pembrolizumab, Lenvatinimib, cetuximab, vismodegib or survivin-2B peptide alone or in combination with radiotherapy. The most common events were radiation-induced skin injuries, decreased lymphocyte count, dysgeusia (86), myalgia and fatigue (87). Table I provides a summary of the trials evaluating treatment strategies for head and neck carcinoma.