The Fzd receptor interacts with other coreceptors, such as the receptor-like tyrosine kinase (Ryk), the receptor tyrosine kinase-like orphan receptor 2 (Ror2) or the low-density lipoprotein receptor-related protein (Lrp)-5/6, with the consequent activation of Disheveled (Dvl) and the downstream pathways ^[1][3]. Generally, cytoplasmatic β-catenin is phosphorylated by a complex formed by glycogen synthase kinase 3β (Gsk3β), adenomatous polyposis coli (Apc), casein kinase 1α (Ck1α) and Axin; β-catenin phosphorylation leads to its degradation by proteasome ^[2][3][5,6]. β-catenin is stabilized when the degradation complex is inhibited by Dvl following the canonical Wnt pathway activation ^[4][2]. β-catenin translocation into the nucleus allows the interaction with transcription factors, such as lymphoid-enhancing factor/T-cell factor (Lef/Tcf) transcription proteins, thus promoting Wnt target genes transcription ^[5][7]. Canonical Wnt signaling role starts from stem cell differentiation until cell proliferation, both during embryogenesis and adult tissue homeostasis ^[6][8].

The non-canonical Wnt signaling pathways are divided into Wnt/Calcium (Ca²⁺) and Wnt/Planar cell polarity (PCP) pathways ^[1][3]. In particular, in the Wnt/Calcium (Ca²⁺) pathway, the activated Fzd-co-receptor-Dvl complex induces phospholipase C γ, which converts phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), resulting in the increased release of intracellular Ca²⁺. The release of Ca²⁺ leads to the activation of calcium-dependent kinases, such as Ca²⁺-dependent phosphatase calcineurin (CaN), Ca²⁺-calmodulin dependent kinase II (CAMKII) or protein kinase C (PKC) ^[7][9]. The activation of CaMKII may induce the phosphorylation of TGFβ-activated kinase 1 (TAK1), resulting in Nemo-like kinase (NLK) activation. TAK1-NLK pathway stimulation antagonizes the canonical Wnt/β-catenin pathway ^[8][10]; on the other hand, CaN induces the translocation of nuclear factor of activated T-cells (NFAT) family proteins into the nucleus, thus inducing the transcription of their target genes. In the Wnt/PCP pathway, activated Fzd-co-receptor-Dvl complex induces the activation of Rho family small GTPases, including RhoA, Rac and Cdc42 ^[9][11]. Cdc42 and Rac promote the c-Jun N-terminal kinase (JNK) signaling, resulting into the activating protein-1 (AP-1) complex activation ^[10][12]. On the other hand, RhoA induces the activation of Rho-associated kinase (ROCK) ^[11][13]. These pathways result in the regulation of cell motility and polarity ^[12][13][14,15].

Chronic inflammation is a widely recognized risk factor for several skin cancers, especially cutaneous squamous cell carcinoma (cSCC) ^[14][16]. The role of Wnt signaling in inflammation is complex, because it includes both anti- and proinflammatory functions ^[15][17]. Particularly, Wnt signaling would exert its immunomodulation acting on important inflammatory cytokines, such as the nuclear factor kappa B (NF-kB) and its target genes IL6, IL8 and TNFA, encoding tumor necrosis factor-α (TNF-α) ^{[15][16][17][18]}[17,18,19,20]. Wnt signaling alterations are involved in the pathogenesis of cutaneous chronic inflammatory diseases, as well as those affecting the skin, such as psoriasis, and autoimmune diseases ^[16][19][20][18,21,22]. In psoriasis, non-canonical Wnt pathway increases keratinocyte proliferation and secretion of pro-inflammatory cytokines, such as TNF-α, interleukin-12 (IL-12) and (IL-23) ^[21][23]. Moreover, it is important to mention the role of canonical and non-canonical Wnt pathways in regulation of immune cells, particularly T cells and dendritic cells. The non-canonical Wnt pathway promotes migration of T cells via the CXC chemokine ligand-12 (CXCL12)–CXC chemokine receptor-4 (CXCR4) signaling ^[22][24]. Nevertheless, Wnt5a, via non-canonical Ca(2+)/CaMKII /NF-κB signaling, may also induce an abnormal phenotype of dendritic cells, which show an altered response to Toll-like receptor (TLR) ligands ^[23][25]. This phenotype is tolerogenic and characterized by increased production of IL-10 ^[23][25]. On the other hand, the canonical Wnt pathway represses the T regulatory cells function, promoting autoimmune response ^[24][26]. The imbalance of immune responses mediated by Wnt pathways may result in psoriatic inflammation but also in autoimmune disease, such as systemic lupus erythematosus (SLE) or systemic sclerosis (SSc) ^[21][23]. Canonical Wnt pathway is hyperactivated in SLE and plays a role in renal fibrosis of lupus nephritis, promoting the differentiation of T cell in Th17 clones ^[21][23]. An increased activation of Wnt signaling is present also in skin fibroblasts of patients with SSc, leading to skin fibrosis ^[21][23]. The deficiency of Wnt inhibitory factor-1 (WIF1) in fibroblasts of SSc patients is correlated with an hyperactivation of Wnt/β-catenin and, thus, with an increased production of collagen ^[25][27]. It is well known that reactive oxygen species (ROS) play an important role in fibrotic processes in SSc ^[26][28]. Preventing the accumulation of ROS in cultured SSc patient cells restored WIF-1 expression, thus avoiding collagen accumulation ^[25][27]. In conclusion, ROS promote Wnt activation, which contributes to fibrosis ^[25][27].

As in cutaneous inflammatory and autoimmune diseases, the Wnt pathway may modulate inflammatory responses in cutaneous cancers and influence tumor microenvironment (TME), thus promoting tumor development ^[27][29]. Wnt pathway and cancer are in relation to the complement system, which is involved not only in anti-tumor but also in pro-tumorigenic immune responses ^[14][16]. Complement component 3 (C3) and its active form, complement anaphylatoxin (C3a), may promote the epithelial-mesenchymal transition (EMT), thus giving invasive properties by decreasing E-cadherin expression ^[28][30]. C3a effects are also mediated by the transcription factor Twist ^[28][30], which induces the EMT through β-catenin ^[29][31]. In vitro experiments showed that exposure to C3 induces cyclin D1 and metalloproteases up-regulation which promote proliferation and migration of cSCC cells ^[30][32]. Moreover, C3a exposure stimulates β-catenin and Sox-2, a transcription factor which regulates cell stemness and induces pluripotent stem cells; in fact, C3a receptor silencing led to the down-regulation of β-catenin and Sox-2 with the consequent decrease of tumor volume ^[30][32]. The most important contribution of Wnt signaling to pro-tumorigenic inflammation is not limited to the complement system but also concerns T cells function: the thymic stromal lymphopoietin (TSLP) is a pro-inflammatory cytokine which antagonizes skin carcinogenesis by regulating the functions of CD8 and CD4 T cells ^[31][33]. TSLP-deficient mice show pro-tumorigenic inflammation and a predisposition to develop tumor growth through Wnt/β-catenin signaling involvement ^[31][33]. In fact, Wnt signaling may influence cancer immune-surveillance and facilitate a tumor immune escape, by reducing the recruitment of dendritic cells and by impairing the activity of T regulatory cells and cytotoxic T lymphocytes ^[32][33][34,35]. Tumors responding better to immunotherapy are characterized by a T cell-inflamed tumor microenvironment (TME), namely infiltrating antigen-specific T cells ^[33][35]. The TME may influence the growth and progression of tumors ^[33][35]. The activation of Wnt/β-catenin pathway prevent T-cell infiltration and activity in TME ^[33][35]. This results in progression of tumors and resistance to immunotherapy ^[33][35]. There are three main mechanisms underlying tumor immune escape by the Wnt/β-catenin pathway. First, the canonical Wnt pathway induces the activating transcription factor 3 (ATF3), thus inhibiting the transcription of C-C motif chemokine ligand 4 (CCL4) in a mouse model. This results in defective infiltration and activation of dendritic cells and T-cells. Another mechanism involved in immune escape concerns the crosstalk between tumor cells and tumor-associated macrophages (TAMs). Tumor cells may stimulate IL-1β production in TAMs via Snail, a transcription factor of canonical Wnt pathway. In turn, IL-β may increase the availability of β-catenin in tumor cells. Finally, canonical Wnt pathway may influence the activity of T regulatory cells, enhancing their survival ^[33][35]. A combination therapy based on the use of immune check point inhibitors plus Wnt signaling inhibitors may improve antitumor immunity ^[34][36].