Melanoma arises from the uncontrolled growth of melanocytes, the pigment-producing cells of the skin, and is strongly linked to ultraviolet radiation exposure, chronic irritation, and friction. Because these tumors invade and spread early, many patients are diagnosed only after distant metastases have taken hold. Yet melanoma carries an unusually high mutational burden, and that burden makes it highly visible to the immune system. It was precisely this immunogenicity that made melanoma the first cancer in which modern immunotherapy was tested, beginning with the approval of interleukin-2 for metastatic disease in 1998. That early success came with a heavy price: interleukin-2’s toxicity was so severe that its use remains confined to a handful of specialized centers.

The true turning point came with immune checkpoint blockade. James Allison’s work on cytotoxic T lymphocyte-associated protein 4, or CTLA-4, produced ipilimumab, an antibody that releases a molecular brake on T cells and slows tumor growth. Subsequent discoveries of programmed cell death protein 1 (PD-1), its ligand PD-L1, T-cell immunoglobulin and mucin domain 3 (TIM3), and lymphocyte activation gene 3 (LAG3) expanded the arsenal. The numbers tell a striking story: objective response rates climbed from roughly 6 to 19 percent with ipilimumab alone, to 21 to 44 percent with the PD-1 inhibitor nivolumab, and to 53 to 61 percent when anti-PD-1 and anti-CTLA4 antibodies were combined in advanced melanoma.

At the heart of these therapies lies the tumor microenvironment, the cellular ecosystem surrounding a tumor, and the review devotes detailed attention to how its inhabitants decide the fate of immunotherapy. Cytotoxic CD8-positive T cells are the primary killers, releasing perforin and granzymes to destroy tumor cells, but their activation depends on helper CD4-positive T cells. The Th1 subset of helper cells supports cytotoxicity and produces the inflammatory signals interferon-gamma and tumor necrosis factor-alpha, which directly kill tumor cells. By contrast, Th2 cells secrete cytokines such as interleukin-4 and interleukin-13 that suppress cytotoxic function, while regulatory T cells inhibit immune activity outright. Memory T cell populations add another layer: in mouse models of metastatic melanoma, circulating memory CD8-positive T cells not only halted lung lesions but also provided durable protection against spread to lymph nodes.

B cells, often overlooked in cancer immunology, are emerging as important players. In melanoma, they gather within tertiary lymphoid structures inside tumors, where they enhance antigen presentation, amplify cytokine signaling, and produce tumor-specific antibodies associated with better outcomes and stronger responses to checkpoint inhibitors. Laboratory studies show that when human B cells are exposed to melanoma secretions, they develop into plasmablast-like cells that release the chemokines CCL3, CCL4 and CCL5, attracting T cells and boosting PD-1-positive T cell activation. Notably, the abundance of these cells in pretreatment tumors can predict how patients will respond to checkpoint blockade.

The innate immune system supplies both allies and saboteurs. Natural killer cells destroy tumor cells directly and recruit other immune players through secreted signals, making them targets for both checkpoint drugs and adoptive transfer strategies. Dendritic cells, the only immune cells capable of activating naive T cells, can be harvested from patients, loaded with tumor antigens in the laboratory, and returned as therapeutic vaccines. Macrophages, meanwhile, display remarkable plasticity: M1-like tumor-associated macrophages fight the tumor, while M2-like subsets promote progression and immune suppression, and a major therapeutic goal is reprogramming them toward the anti-tumor state. Against these allies stand myeloid-derived suppressor cells, whose high frequency in the blood correlates with worse outcomes on checkpoint therapy, and cancer-associated fibroblasts, which sculpt an immunosuppressive environment by releasing factors that dampen T cell and natural killer cell function, often in pathways tied to BRAF mutations.

Biotherapies represent the newest frontier. Adoptive cell therapy transfers living lymphocytes, expanded or gene-edited outside the body, back into patients, and includes tumor-infiltrating lymphocyte therapy, T cell receptor therapy, and chimeric antigen receptor T cells. In a pivotal trial, patients with advanced melanoma who received tumor-infiltrating lymphocyte therapy lived significantly longer without progression than those treated with ipilimumab. Engineered innovations are pushing further: an injectable, photocurable gelatin methacryloyl hydrogel that serves as a local depot for CAR-T cells significantly extended survival in mice compared with conventional delivery, and a 12-patient trial of GD2-specific CAR-T cells found the approach well tolerated with no dose-limiting toxicities. RNA vaccines add another weapon, with the liposomal FixVac vaccine targeting four shared melanoma antigens and driving durable responses in patients with unresectable disease. Oncolytic viruses complete the picture: talimogene laherparepvec, marketed as Imlygic, is injected directly into tumors every two weeks, where it destroys cancer cells and simultaneously provokes a systemic immune attack.

Yet the revolution is incomplete. Up to 60 percent of melanoma patients treated with checkpoint inhibitors experience severe immune-related adverse events, as the same brakes that restrain T cells against tumors also protect healthy organs, and delayed adverse events can be fatal. Resistance is equally troubling: PD-1 antibodies alone produce response rates of only 19 to 45 percent in metastatic melanoma, and roughly a third of initial responders eventually relapse. Mechanisms of resistance include melanoma dedifferentiation, loss of antigen presentation, immune cell exclusion linked to PTEN loss, myeloperoxidase activity, and metabolic rewiring. Promising countermeasures are emerging, among them tilsotolimod, which triggers a localized type 1 interferon response, and inhibitors of the kinase TBK1, which lower the threshold for T cell cytotoxicity and enhance responses to PD-1 blockade in patient-derived models.

The clearest path forward, the review concludes, is rational combination. Pairing nivolumab with ipilimumab produced a median overall survival exceeding 60 months, compared with 36.9 months for nivolumab alone and 19.9 months for ipilimumab alone. The LAG3 inhibitor relatlimab combined with nivolumab, now FDA-approved as first-line therapy for metastatic melanoma, extended progression-free survival to 10.1 months versus 4.6 months with PD-1 blockade alone. Combining immunotherapy with targeted drugs such as the BRAF inhibitor dabrafenib and MEK inhibitor trametinib, with radiotherapy, which can provoke abscopal responses at distant tumor sites, and with agents like guadecitabine that deplete suppressor cells, all show clinical benefit. Neoadjuvant approaches are particularly striking: giving nivolumab and relatlimab before surgery achieved a pathologic complete response rate of 57 percent, and responding patients enjoyed one-year relapse-free survival of 100 percent. The authors argue that the future lies in precision medicine, using biomarkers to match each patient with the right combination, converting immunologically cold tumors into hot ones, and ensuring that the remarkable gains of the immunotherapy era reach every patient rather than a fortunate few.

Subject of Research: Immunotherapy mechanisms and combination strategies in malignant melanoma

Article Title: Insights for the immunotherapy in malignant melanoma: a new revolution

Article References: Xuan, J., Gao, Z., Wei, C., & Gu, J. (2024). Insights for the immunotherapy in malignant melanoma: a new revolution. Clinical Cancer Bulletin, 3(1), Article 21. https://doi.org/10.1007/s44272-024-00026-8

Image Credits: AI Generated

DOI: 10.1007/s44272-024-00026-8

Keywords: melanoma, immunotherapy, immune checkpoint inhibitors, PD-1, CTLA-4, tumor microenvironment, adoptive cell therapy, TIL therapy, RNA vaccines, oncolytic virus, combination therapy, drug resistance