2.3.2.2 Current treatment
Melanoma is a highly malignant tumor derived from melanocytes，which characterized by high invasiveness，early metastasis，and strong resistance to conventional radiotherapy，chemotherapy and immunotherapy.Now the current status and prospects of melanoma treatment are summarized.
1.Traditional treatment
（1）Surgical treatment：After the diagnosis of melanoma，the primary lesion should be completely removed by surgery as soon as possible.The scope of surgical resection is determined in principle according to the Breslow thickness of the tumor，and should include subcutaneous tissue and reach the fascia.And for patients with melanoma，it is recommended to perform preventive lymph node dissection and sentinel lymph node biopsy.However，surgical treatment can only be effective for some early melanoma patients.Nearly 60％of melanoma patients still die of recurrence and metastasis.Therefore，for melanoma patients without metastasis but with a high risk of recurrence，systemic immunotherapy is needed after surgical resection，which can effectively suppress the formation of clinically undetectable microscopic lesions and metastases.
（2）Chemotherapy and radiotherapy：Chemotherapy is the first choice for metastatic melanoma.In 2011，the US FDA approved dacarbazine，which is still the most effective drug，as the chemotherapy drug for metastatic melanoma.However，the efficiency of dacarbazine is only 20％.Although radiotherapy can relieve the obstruction symptoms and inhibit distant metastases of melanoma，it cannot prolong the survival time of patients.Moreover，melanoma cells are resistant to radiotherapy，which may be due to DNA damage have been repeatedly happened to melanoma cells，and therefore have effective DNA repair capabilities.
（3）Cytokines：①Interferon：Many clinical trials have proved that the melanoma patients combined with high-dose interferon after early excision can effectively reduce the recurrence rate and prolong the survival period.However，this therapy is expensive and has serious side effects.②Recombinant interleukin-2（IL-2）：IL-2 is an inflammatory cytokine and is the first immunotherapeutic agent approved by the US FDA for the treatment of metastatic melanoma.In eight phase Ⅱ clinical trials，a total of 270 patients，approximately 15％of the patients experienced overall remission after high-dose IL-2 administration，and approximately 4％-6％of the patients experienced long-term complete remission.However，high-dose IL-2 treatment can cause serious adverse effects such as hemodynamic shock and respiratory failure.
（4）Tumor vaccines：Most tumor-associated antigens used in tumor vaccine research can be classified as follows：①autoantigens，molecules distributed in tumor tissues and overexpressed tumor antigens；②cancer testis antigens，tumor-associated antigens with restricted expression in the testis and placenta.Vaccination can induce the immune system to reject tumors，but the overall response rate is 4％-5％for melanoma.
2.Systemic immunotherapy(https://www.daowen.com)
（1）Adoptive cell therapy：The reinfusion therapy of tumor-infiltrating lymphocytes.Tumor-infiltrating lymphocytes of melanoma patients are isolated and modified in vitro（such as adding some antigen and cytokines to stimulate），thereafter screening and expanding the active immune effector cells that can kill cancer cells，and then reinfuse them back to the patients.This method is effective for some patients with advanced melanoma，and complete responders rarely relapse，even complete clinical remission can be reached.However，only 40％-50％of the patients with surgery can obtain tumor-infiltrating lymphocytes.Moreover，the method has strong personalization and a long preparation period，thus clinical application is still a challenge.Another method is to use engineered peripheral blood lymphocytes with chimeric antigen receptors（CARs）.CARs are T cell receptors，costimulatory molecules or single-chain antibodies that bind to tumor-associated antigens with high TCR affinity.CARs'recognition of tumor-associated antigens is not restricted by HLA，and the clinical response rate is high in hematopoietic malignant tumors and solid tumors.However，due to the presence of cross-reactions，this treatment method has serious toxic effects in important normal tissues.
（2）Molecular targeted therapy：In recent years，with the improvement insight on the pathogenesis of melanoma，it has been found that the formation of melanoma is related to the abnormal activation of some signaling pathways.For example，40％-60％of melanomas have BRAF gene mutation，which subsequently causes the mitogen-activated protein kinase（MAPK）pathway to constitutively activate the downstream signals.Therefore，the emergence of a series of new drugs targeting signaling pathways，such as vemurafenib and dabrafenib，has opened new insights for targeted therapy of melanoma.BRAF and MEK inhibitors entered the 2019 edition of the US NCCN guidelines for the diagnosis and treatment of melanoma.The BRAF and NRAS genes mutation rates among Chinese melanoma patients are low，and the main gene profiles are to be studied.For patients with metastatic melanoma who cannot tolerate immunotherapy，targeted therapy with BRAF/MEK is preferred.This method has a high initial response rate and improved survival.The limitations are the short average length of the response period and the high recurrence rate.
（3）Immune checkpoint inhibitors：Immune checkpoints are the molecules involved in maintaining immune homeostasis，which help maintain the tolerance of the periphery to own molecules，and can suppress or enhance immune responses.The well-known inhibitory immune checkpoints are CTLA-4 and PD-1，which have made important breakthroughs in clinical practice.The US FDA has approved melanoma immunotherapy drugs in recent years including ipilimumab（anti-CTLA-4）in 2011，pembrolizumab（anti-PD-1）in 2014，and nivolumab（anti-PD-1）in 2016.Immunotherapy has greatly improved that raised the survival rate of melanoma patients and brought hope to the clinical treatment of melanoma.Pembrolizumab has become the standard first-line treatment for advanced melanoma，as it can block disease progression for a long time and improve overall survival，and 85％of the patients still do not progress 2 years after drug withdrawal.Immunotherapy has fundamentally changed the past dilemma of melanoma，making patients see the hope of“healing”.In Europe and the United States，skin melanoma is more likely to be found，whereas the proportion of extremity and mucosal melanoma in China exceeds 50％.It has been proved that pembrolizumab has equal effect for extremities and mucosal melanoma.For current metastatic melanoma，anti-PD-1+/-CTLA-4 treatment improves overall survival，response rate，and durability of response and is the first-line treatment.The advantages of immune checkpoint blockade（ICB）treatment include significant improvement in overall survival and long-lasting response.The limitation is that only some patients respond to ICB and immune-related side effects cannot be ignored.
（4）New immunotherapy strategies（nano，microneedles，etc.）：Conventional therapies（e.g.，dacarbazine，interferon，and interleukin-2）are limited by low response rates and will not improve overall survival.New targeted therapies（e.g.，vemurafenib，dabrafenib，and trametinib）have a high initial response rate and significantly improve overall survival，but usually relapse within 6-9 months.Although immunotherapy（e.g.，ipilimumab，pembrolizumab，and nivolumab）can obtain long-term and long-lasting responses，it is only effective for some patients，and the incidence of adverse events is very high.For all this，in the past decade，with the advent of molecular targeted therapy and immunotherapy，there has been unprecedented clinical progress in the field of melanoma therapy.However，the clinical treatment of melanoma still faces huge challenges.With the rapid development of nanotechnology for cancer treatment，nanotherapy provides important prospects for overcoming these shortcomings.The antitumor applications of nanomedicine are diverse，including nanomedicine directly killing tumor cells，or as a carrier of chemotherapy and gene therapy.There are also applications of photothermal therapy（PTT）and photodynamic therapy（PDT）based on nanomaterials.In addition，nanomedicines can passively or actively deliver effect structures to tumor sites，thereby increasing treatment specificity and reducing side effects.Several nanomedicines have been approved by the US FDA for clinical treatment，and other nanomedicines currently in preclinical or clinical trials have shown potential for tumor therapy.We expect that the application of nanocarriers will change the landscape of melanoma treatment in the future（see extended reading 1）.
（5）Combination therapy：Compared with the use of any one therapy alone，the combination of anti-CTLA-4 and anti-PD1 antibodies has a better antitumor response.Combination therapy is associated with progression-free survival（PFS）and overall survival.In addition，advanced melanoma is one of the few cancers that often metastasize to the brain，and combined immunotherapy can reduce melanoma brain metastases.There are several new immune checkpoint inhibitors are currently undergoing preclinical and clinical stages，including LAG-3，TIM3，IDO，FOXP3，CSF1R inhibitors，etc.They can be used for melanoma patients who associated with changes in PD-L1 levels and show poor response to ICB single medication.They can also be used in combination with different checkpoint inhibitors.Oncolytic virus combined with ICB can promote T cell infiltration in the tumor and improve the response rate of immunotherapy.Anti-PD-（L）1 combined with BRAF/MEK targeted therapy has shown improved response rates in early clinical trials，but the incidence of adverse effects has increased.PD-1 or BRAFi/MEKi is the current first-line option for adjuvant therapy after melanoma resection.Anti-CTLA-4 monoclonal antibody and anti-PD-1 monoclonal antibody are approved for adjuvant treatment of stage Ⅲ and low metastatic stageⅣ resectable melanoma.BRAFi/MEKi（dabrafenib and trametinib）is approved for the adjuvant therapy of stageⅢmelanoma.