Melanoma is one of the most common skin cancers, and it is notorious for its heterogeneity and propensity to metastasize to distant organs ^[1][2][1,2]. Although the treatment options of melanoma have improved in recent years, patients with advanced malignant melanoma still have poor prognosis, as measured by progression-free and overall survival [3].

Molecularly targeted therapies are characterized by their specificity to interfere with key molecules of aberrant signaling pathways, particularly those of tumor growth and survival. Over 60% of primary cutaneous melanomas and over 50% of metastatic melanomas harbor the activating murine sarcoma viral oncogene homolog B (BRAF) mutation ^[4][5][4,5]. To that end, the continuous activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling by the BRAF^V600E mutation is common and independent from extracellular stimulation ^[6][7][6,7]. Melanoma is a tumor mass that contains supporting stroma (fibroblasts, endothelial cells, and immune cells), the extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles), rather than a mass of monolithic tumor cells.

Apart from its adverse effects, chemotherapeutic agents remain the best option for cancer therapy to date. Depending on the tumor stage and patient tolerability, chemotherapy can be given alone or in combination with surgery or radiotherapy ^[8][9][156,157]. The discovery of active mutations, which are involved in tumor initiation and development, such as epidermal growth factor receptor (EGFR), p53, c-Kit and BRAF ^[10][11][158,159], compelled researchers to extensively study the reliability of such mutations as selective therapeutic targets ^[12][13][14][160,161,162]. Although the successful targeting of these mutations improves overall survival of melanoma patients, acquired tumor resistance develops and increases continuously ^[15][16][163,164]. Consequently, tumor relapse and low life quality of patients are common.

During tumor development, cancer cells and the components of the tumor microenvironment are continually adapting to the environmental conditions to promote tumor growth, progression, and treatment resistance ^[17][165].

Tumor microenvironment components play a significant role in cancer progression, maintenance, and resistance to anticancer agents ^[18][19][128,166]. The crosstalk between tumor cells and their microenvironment is essential for acquiring and maintaining tumor cell characteristics, such as sustaining proliferative signaling, resisting cell death, inducing angiogenesis, activating invasion, metastasis, triggering tumor-promoting inflammation, and avoiding immune destruction ^[20][21][22][167,168,169]. This dependence on the tumor microenvironment offers an opportunity for the development of therapeutic approaches by targeting the components of the tumor microenvironment or their dependent signaling pathways. Based on the increased understanding of the crucial roles of the tumor microenvironment on tumor development and therapeutic resistance, many efforts have been made to target tumor microenvironment components for therapeutic benefit in cancer patients ^[23][170]. Importantly, targeting the components of the tumor microenvironment has a significant therapeutic advantage over the direct targeting of cancer cells, as cancer cells are infamous for their genomic instability that is a main cause for the development of drug resistance ^[24][25][132,171]. In contrast, the non-tumor cells of the tumor microenvironment are genetically more stable in nature and more susceptible ^[26][172].

Over the recent decade, accumulating evidence revealed that CAFs, the major component of stroma in malignancies, play an essential role in tumor proliferation, progression, and treatment resistance ^[23][27][170,173]. Thus, CAFs are suggested to be a potential therapeutic target for the treatment of different tumor types including melanoma. Many drugs targeting CAFs have been developed and tested in preclinical and/or clinical studies. The most identified targets of CAFs are the fibroblast activation protein (FAP), vitamin D receptor (VDR), and platelet-derived growth factor receptor (PDGRF) ^[28][29][30][174,175,176].

FAP is a serine protease with dual enzymatic activities and is overexpressed in CAFs and in many other tumor types ^[31][177]. The G-protein-coupled receptor 77 (GPR77) is a potential FAP surface target and is specifically expressed in CAFs ^[28][29][30][174,175,176]. In addition to its important role in tumor development, the overexpression of FAP on CAFs is mostly associated with poor prognosis ^[32][33][178,179].

Accumulating evidence suggests that vitamin D does not only suppress cancer cells but also contributes to the modulation of tumor stromal cell genes and triggers tumor angiogenesis, progression, and metastasis ^[34][35][180,181]. These observations suggest that the vitamin D receptor is a promising target for the treatment of tumors such as melanoma. 

Several studies suggested that an important role exists for PDGF in the regulation of the recruitment and phenotypic character of the tumor stroma ^[36][37][114,182]. PDGF-BB has been shown to trigger the formation of growth-promoting stroma in melanoma ^[36][37][114,182]. Inhibition of vascular endothelial growth factor-A (VEGF-A) production promotes tumor cells to secrete PDGF-AA to attract stromal fibroblasts, which can be stimulated to produce VEGF-A and induce angiogenesis ^[38][39][183,184]. To that end, PDGRF is essential in promoting tumor growth by both direct growth stimulatory effects and promotion of angiogenesis and pericyte recruitment ^[40][41][185,186], and it is therefore a promising therapeutic target for tumor treatment.

Tumor-associated macrophages (TAMs) have also emerged as therapeutic targets in melanoma treatment. TAMs belong to stromal cells and are abundant in the tumor microenvironment ^[42][43][187,188]. TAMs are mostly associated with poor clinical outcomes in cancer patients ^[44][45][189,190]. Accordingly, colony-stimulating factor 1 receptor (CSF1R) signaling has gained more attention as a therapeutic target. CSF1/CSF1R has been reported to play a central role in the proliferation, differentiation, and function of macrophages ^[46][47][191,192]. Therefore, inhibition of CSF1R signaling is expected to block the function of TAMs. Consequently, several inhibitors (PLX3397, JNJ-40346527, PLX7486, and ARRY-382) and neutralizing antibodies (RG7155, IMC-CS4, and FPA008) have been developed and tested for their clinical relevance as CSF1R inhibitor-based therapies ^[46][48][191,193]. Many preclinical and clinical investigations have demonstrated that inhibition of CSF1R results in the depletion of TAMs and microglia ^[49][194].

Tumor-associated neutrophils (TANs) are also therapeutic targets in melanoma treatment. TANs originate from myeloid precursors and are the most abundant population of leukocytes as well as the first responders of innate immunity ^[28][50][174,195]. TANs are one of the most important stromal cells in the tumor microenvironment and play active roles in tumor progression and metastatic dissemination ^[51][52][196,197] TANs mediate their pro-tumor roles by stimulating ECM and inflammation in the tumor microenvironment ^[53][198]. TANs are characterized by their ability to release granules containing various proteases, such as matrix metalloprotease 9 (MMP-9) ^[54][55][199,200] and neutrophil elastase ^[56][57][201,202]. Consequently, TANs can remodel ECM and promote tumor invasion ^[45][58][190,203]. In addition to the production of proinflammatory cytokines/chemokines, TANs also produce immunosuppressive factors, including arginase 1 and TGF-β ^[59][204]. These immunosuppressive factors are mainly involved in the suppression of adaptive immunity ^[60][205] as well as in the release of HGF to promote tumor progression ^[61][206]. Thus, targeting TANs is expected to be a potential therapeutic strategy for tumor treatment ^[62][207]. One of the most promising targets is the chemokine receptor 2 (CXCR2), which is known to be a critical regulator for neutrophil mobilization ^[63][208]. Preventing the interaction between CXCR2 and its ligand (CXCL8) by small molecular inhibitors or antibodies has been shown to exert anti-tumor activities and improves the treatment efficacy of chemotherapy ^[63][64][208,209]. Several clinical trials such as SX-682 have been suggested as potent inhibitors of CXCR1/2. SX-682 has been tested for its clinical relevance in several studies ^[65][210]. SX-682 can block tumor cells by attracting myeloid-derived suppressor cells (MDSCs), which increases therapeutic efficacy when combined with immunotherapies ^[65][210].

Inflammation is a consequence of the innate immune response reacting to disturbed tissue homeostasis. Chronic inflammation is one of the common hallmarks of cancer and plays an essential role in the enhancement of tumor development and progression ^[66][67][211,212]. Thus, targeting inflammation is expected to be a promising approach for cancer therapy. Data obtained from a large population study revealed that aspirin is an anti-inflammatory drug found to significantly reduce cancer risk ^[68][69][213,214]. Both macrophages and tumor cells are characterized by their potency to produce proinflammatory cytokines and inflammatory mediators and thereby sustain tumor cell proliferation and survival ^[70][71][215,216], immune evasion ^[72][217], angiogenesis ^[73][74][218,219], ECM remodeling ^[75][76][220,221], metastasis ^[77][222], chemoresistance ^[73][78][218,223], as well as radio-resistance ^[79][224]. To that end, targeting the key mediators of proinflammatory pathways and/or the main regulators (e.g., NF-κB and STAT3) of inflammatory cytokines (e.g., IL-1, TNF, and IL-6) is expected to inhibit cancer-promoting inflammation. Unfortunately, few antibodies/inhibitors exhibited anti-tumor activities in preclinical studies; thus, only a few candidates are under investigation in early-stage clinical trials ^[80][81][96,225]. Therefore, the main challenge of targeting inflammation is how to develop selective anti-inflammatory approaches without impairing anti-tumor immunity.

Other components of the tumor microenvironment can function as targets for melanoma treatment. These include B lymphocytes, regulatory T cells (Treg), adipocytes, mesenchymal stem cells, and exosomes ^[82][83][226,227]. These tumor microenvironment components have been shown to influence tumor progression and therapeutic responses ^[84][228]. Tregs are characterized by the expression of the transcription factor fork head box protein p3 (Foxp3) that is involved in the suppression of anticancer immunity ^[85][86][87][229,230,231]. Consequently, the protective immunosurveillance of tumors can be impaired, resulting in the loss of effective antitumor immune responses. Functionally, the tumor microenvironment can trigger the suppression of Tregs by the upregulation of immune checkpoint proteins. Thus, targeting immune checkpoint molecules (e.g., CTLA-4, TIGIT, PD-1, and GITR) on Tregs may have a therapeutic impact on the treatment of melanoma.

The role of inhibitory receptors in the regulation of both innate and adaptive immunity in chronic viral infections and cancer has been studied ^[88][89][232,233]. Chronic antigen stimulation mainly results in the modulation of T cell dysfunction and the upregulation of inhibitory receptors such as programmed cell death-1 (PD-1) and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) ^[90][91][234,235]. In addition to the expression of the ligands of the inhibitory receptors by tumor cells, the tumor microenvironment contains the required antigen-presenting cells (APCs) ^[92][93][236,237]. TIGIT has been reported to play a critical role in the reduction of both adaptive and innate immunity against tumors ^[90][91][234,235]. The clinical relevance of monoclonal antibodies targeting the inhibitory receptors has been reported in several studies ^[94][238].

T lymphocyte-associated antigen 4 (CTLA-4) is one of the first identified inhibitors of immune checkpoint on Tregs. Targeting CTLA-4 by anti-CTLA-4 antibodies has been shown to block the tumor suppressive function of Tregs and ultimately to release the cytotoxicity function of effector cells.

Programmed cell death 1 (PD-1) signaling is known to be hijacked by cancer cells to escape immune surveillance ^[95][96][97][239,240,241]. The intrinsic expression of PD-1 has been reported to contribute to the development of tumor monoresistance ^[98][99][242,243]. In melanoma cells, the activation of PD-1 by its ligand PD-L1 has been shown to trigger the activation of downstream mammalian targets of rapamycin signaling leading to tumor growth ^[100][244]. Thus, targeting the PD-1/PD-L1 axis has shown enormous success in a variety of human cancers ^[101][102][245,246]. Due to its durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, antibody-mediated blockade of PD-L1 is clinically relevant.

In the last two decades, the treatment of a variety of malignancies based on immune checkpoint modulation has been promising compared to available therapeutic modalities. However, checkpoint modulation has been reported to be less therapeutically effective in cancers with an immunosuppressive microenvironment ^[103][104][247,248]. Although the advent of immunomodulatory agents has led to improved responses in tumor patients, as evidenced by achieving long-lasting tumor remission ^[105][106][249,250], many exhibit brief or no response to available immunomodulatory agents ^[107][108][251,252]. Thus, the development of alternate therapeutic strategies is of great interest. In recent years, the modulation of the tumor microenvironment, in the context of the local metabolites, has been suggested as a promising strategy in cancer immunotherapy ^[109][253]. For example, live tumor-targeting bacteria have emerged as a treatment for solid tumors, compared with immunotherapy and targeted therapy ^[110][254]. Likewise, the clinical investigation of live engineered bacteria for metabolic modulation has been reported ^[111][255].

Oncolytic viruses have also been suggested as a promising alternative therapy for cancer treatment, particularly for refractory cancers with a 5-year survival rate of 5%, such glioblastoma ^[112][256]. While viral-mediated oncolysis has been hypothesized to spread to all cancer cells within the tumor, this has not been shown in clinical studies so far. Clinical data revealed that the development of an antiviral immune response and limited antitumor immunity limit the efficiency of virotherapy when utilized as a monotherapy ^[113][114][257,258]. Apart from the abovementioned limitations of virotherapy, the mechanisms of viral infection, replication, and tumor necrosis have the potential to destruct the immunosuppressive tumor microenvironment and ultimately enhance T cell reactivity against cancer neo-antigens ^[115][259].

The advantage of oncolytic virotherapy over checkpoint-protein-based immune therapy is attributed to the ability of oncolytic virotherapy to circumvent the immune evasion mechanisms of the tumor ^[116][117][260,261]. Oncolytic virotherapy can also improve the treatment outcome of tumor patients by the stimulation of host immune system and/or direct lysis of tumor cells.