Melanoma

Melanoma is the most serious form of skin cancer, with approximately 325,000 new cases diagnosed worldwide each year. The disease develops when melanocytes—the cells that produce skin pigment (melanin)—undergo genetic mutations that cause them to grow and divide uncontrollably. UV radiation from sun exposure or tanning beds is the primary risk factor, causing DNA damage that can trigger these cancer-causing mutations, though melanoma can also develop in areas with little sun exposure and occasionally occurs in people with minimal UV exposure history. About half of melanomas have mutations in a gene called BRAF, while others harbor different genetic changes in genes like NRAS, KIT, or NF1 that drive cancer growth. Melanoma typically appears as a new dark spot on the skin or a change in an existing mole—doctors use the "ABCDE" criteria (Asymmetry, Border irregularity, Color variation, Diameter over 6mm, Evolution or change) to identify suspicious lesions. While most melanomas develop on the skin (cutaneous melanoma), rarer forms can occur in the eye (uveal melanoma), on mucous membranes, or on the palms, soles, or under nails (acral melanoma). When caught early as a superficial growth, melanoma is highly curable with simple surgical removal, but if allowed to grow deeper into the skin or spread to lymph nodes or distant organs, it becomes much more challenging to treat.

Surgery remains the primary treatment for localized melanoma, with wide excision (removing the tumor plus surrounding tissue margin) curing most early-stage cases. For melanomas with concerning depth or features, sentinel lymph node biopsy checks whether cancer has spread to nearby lymph nodes. The melanoma treatment landscape has been revolutionized over the past decade by two major advances: immunotherapy and targeted therapy. Checkpoint inhibitors—drugs including pembrolizumab, nivolumab, and ipilimumab that help the immune system recognize and attack cancer cells—have transformed outcomes for advanced melanoma, with some patients achieving long-lasting remissions lasting years. These drugs can be used alone or in combinations, with dual immunotherapy offering higher response rates but also more side effects. For the roughly 50% of patients whose melanomas have BRAF mutations, targeted therapy combinations (like dabrafenib plus trametinib or vemurafenib plus cobimetinib) block the abnormal proteins driving cancer growth, often producing rapid tumor shrinkage. After surgery for high-risk melanomas, adjuvant therapy with either immunotherapy or targeted drugs (if BRAF-mutated) significantly reduces recurrence risk. Early-stage melanomas have excellent cure rates—over 99% of people with localized disease are alive five years later. Even for advanced melanoma, five-year survival rates have increased from less than 20% before these new treatments to over 50% now, with many patients living much longer.

Brain metastases develop in 40-60% of people with advanced melanoma during their illness, and while newer treatments reach the brain better than older chemotherapies, managing brain involvement while controlling disease elsewhere remains challenging. Not all patients respond to immunotherapy—about 40-50% respond to single-agent checkpoint inhibitors and 60-70% to combination immunotherapy, leaving a significant proportion needing alternative approaches. Resistance to targeted therapies typically develops within 1-2 years as tumors acquire new mutations that allow them to escape drug effects, requiring switches to immunotherapy or other treatments. Rare melanoma subtypes including uveal (eye), mucosal, and acral melanomas respond less well to standard immunotherapy and often lack the BRAF mutations that make targeted therapy possible, leaving fewer effective options. Immunotherapy can cause immune-related side effects where the activated immune system attacks normal tissues, affecting organs including the gut, liver, lungs, endocrine glands, and occasionally the heart or nervous system—these range from manageable to serious and sometimes require permanent discontinuation of treatment. Predicting before starting therapy which patients will respond to immunotherapy versus targeted therapy would enable more personalized treatment selection and help avoid ineffective treatments. Some patients experience long-term effects from immunotherapy including fatigue, joint pain, or ongoing endocrine problems requiring hormone replacement.

LAG-3 inhibitors represent a new class of immunotherapy targeting a different immune checkpoint, with relatlimab combined with nivolumab already approved for advanced melanoma and additional combinations in Phase 3 trials. Tumor-infiltrating lymphocyte (TIL) therapy—where immune cells are extracted from patients' own tumors, multiplied to billions in the laboratory, and reinfused—showed strong results in trials and lifileucel recently received approval, offering another option for advanced disease. Personalized cancer vaccines created from each patient's specific tumor mutations are in Phase 2 and Phase 3 trials, designed to train the immune system to recognize and attack cancer cells based on their unique features. Novel oncolytic viruses—engineered viruses that selectively infect and kill cancer cells while stimulating immune responses—are being tested, building on T-VEC (already approved for injectable lesions). New targeted therapies for non-BRAF melanomas are advancing, including drugs for NRAS-mutated melanomas and KIT-mutated melanomas (which are more common in acral and mucosal types). Next-generation immunotherapy combinations pairing checkpoint inhibitors with other immune-stimulating agents or with targeted therapies are in trials. Regional therapies including isolated limb infusion delivering high-dose chemotherapy directly to melanomas on arms or legs are being refined. Trials are evaluating shorter duration immunotherapy in the adjuvant setting to reduce side effects while maintaining benefit, and testing whether neoadjuvant therapy (treatment before surgery) improves outcomes for high-risk melanomas.

CAR-T cell therapy, which has transformed blood cancer treatment, is being adapted for melanoma with researchers engineering immune cells to recognize melanoma markers and developing strategies to help them penetrate and survive in the tumor microenvironment. Scientists are creating next-generation checkpoint inhibitors targeting newly discovered immune pathways including TIGIT, TIM-3, and others that could benefit patients who don't respond to current immunotherapy. Bispecific antibodies that simultaneously bind melanoma cells and T cells to force immune engagement are in development. mRNA vaccine technology—the same platform used for COVID-19 vaccines—is being applied to cancer vaccines, offering rapid manufacturing of personalized treatments targeting each patient's specific tumor mutations. Nanotechnology approaches are being developed to improve drug delivery, concentrating treatments at tumor sites while reducing systemic exposure and side effects. Researchers are investigating the tumor microenvironment—the blood vessels, immune cells, and supportive tissue surrounding melanoma—to identify new drug targets and ways to make tumors more responsive to immunotherapy. Scientists are exploring whether gut bacteria influence immunotherapy response, with early studies suggesting that microbiome composition affects treatment outcomes and that modifying intestinal bacteria through fecal transplants or probiotics might improve results. Liquid biopsies detecting melanoma DNA in blood are being refined for earlier detection of recurrence, real-time treatment monitoring, and potentially screening high-risk individuals. Artificial intelligence is analyzing genetic, molecular, and imaging data to predict which treatments will work for individual patients and identify new drug targets. Metabolic therapies targeting how melanoma cells produce energy differently than normal cells are in development. Researchers are working on combination approaches that pair immunotherapy with drugs targeting cancer metabolism, blood vessel formation, or the supportive cells surrounding tumors. Gene editing technologies including CRISPR are being explored to enhance immune cell function and directly target cancer-causing mutations.