Melanoma represents a biologically distinct neoplasm with high immunogenicity, largely due to its elevated mutational burden.

This mutational load, primarily from ultraviolet-induced DNA damage, renders melanoma an ideal candidate for immune-based therapies.

The immune system's ability to recognize tumor-specific neoantigens provides a therapeutic opportunity that has been uniquely leveraged in this malignancy.

Historically, metastatic melanoma carried a grim prognosis, with median overall survival rates rarely exceeding 12 months prior to the advent of immune checkpoint inhibitors. The transformation from palliative intent to potentially curative immunotherapy regimens underscores a new era in oncologic therapeutics.

Checkpoint Inhibitors: Redefining the Immune Landscape

Checkpoint inhibitors targeting PD-1 and CTLA-4 have significantly improved survival outcomes in advanced melanoma. The PD-1/PD-L1 axis is a critical immune checkpoint exploited by tumors to suppress cytotoxic T-cell activity. Agents such as nivolumab and pembrolizumab restore T-cell effector function, allowing for sustained tumor surveillance and destruction.

Combination regimens, such as nivolumab plus ipilimumab, have demonstrated superior response rates compared to monotherapy. The CheckMate 067 study, a pivotal randomized phase III trial, demonstrated a 58% five-year survival rate with combination therapy, compared to 44% with nivolumab alone and 26% with ipilimumab alone. However, immune-related adverse events (irAEs), including colitis, hepatitis, and endocrinopathies, remain a significant management challenge.

Recent studies suggest that treatment sequencing, rather than concurrent administration, may optimize efficacy while mitigating toxicity. According to Dr. Caroline Robert, a leading dermato-oncologist at Institut Gustave Roussy, "the future lies not only in combining immune agents but in refining the timing and patient selection."

Neoantigen Vaccines and Personalized Immunogenic Profiling

Neoantigen-based vaccination strategies represent a shift toward personalized immunotherapy. These vaccines aim to prime the immune system against tumor-specific antigens not expressed in normal tissue, thereby avoiding autoimmunity. Whole-exome sequencing allows identification of unique tumor mutations, which are then synthesized into peptide vaccines.

Clinical trials, such as NEO-PV-01, have shown promising immune responses when combined with PD-1 blockade. In this study, over 60% of patients developed T-cell reactivity to vaccine-targeted neoantigens, correlating with delayed progression.

Advances in mRNA vaccine technology — accelerated by the COVID-19 pandemic — are now being repurposed for melanoma. These platforms allow for rapid, patient-specific vaccine development with enhanced antigen presentation. Moderna and Merck's mRNA-4157/V940, an investigational cancer vaccine in combination with pembrolizumab, has entered Phase III trials following favorable Phase II data showing significant improvement in recurrence-free survival.

Oncolytic Viral Immunotherapy: Dual Mechanism of Action

Talimogene laherparepvec (T-VEC), a modified simplex virus-1 (HSV-1), is engineered to selectively replicate in tumor cells and produce granulocyte-macrophage colony-stimulating factor (GM-CSF), promoting dendritic cell recruitment and T-cell priming. Unlike systemic therapies, T-VEC provides both direct oncolysis and immune stimulation.

Emerging oncolytic viral platforms are being engineered to deliver immune co-stimulatory molecules or checkpoint inhibitors directly into the tumor microenvironment, offering localized immunomodulation. Trials involving RP1 (a proprietary oncolytic HSV engineered to express GM-CSF and GALV-GP-R), in combination with nivolumab, have shown increased TIL (tumor-infiltrating lymphocyte) activity and objective responses in previously refractory melanoma.

Tumor Microenvironment (TME): Overcoming Immune Resistance

Melanoma's resistance to immunotherapy often resides within the immunosuppressive TME. Key components such as Tregs, MDSCs, and inhibitory cytokines (such as IL-10, TGF-β) can blunt T-cell efficacy. Strategies to remodel the TME are underway, including:

- CSF1R inhibitors, which deplete immunosuppressive TAMs.

- IDO1 inhibitors, which block tryptophan metabolism-mediated T-cell suppression.

- TGF-β pathway blockers, now in early-phase trials, to reduce fibrosis and stromal exclusion of immune cells.

Predictive Biomarkers and Precision Stratification

Although PD-L1 expression has been traditionally used as a predictive marker, its reliability in melanoma is limited due to tumor heterogeneity and dynamic expression. Current research is focusing on composite biomarkers integrating:

- Tumor mutational burden (TMB).

- Gene expression signatures related to IFN-γ.

- Spatial TIL mapping via multiplex immunohistochemistry.

A study published in Cell (2024) introduced a machine-learning model that predicts immunotherapy response based on transcriptomic and epigenomic features, achieving 81% accuracy in independent melanoma datasets. Moreover, circulating tumor DNA (ctDNA) is emerging as a non-invasive biomarker to monitor minimal residual disease (MRD) and detect early resistance to therapy. Serial ctDNA measurements can provide real-time insight into treatment efficacy, guiding timely modifications.

Future Directions: Towards Adaptive and Combinatorial Immunotherapy

Next-generation immunotherapies are poised to include adaptive cell therapies, such as tumor-infiltrating lymphocyte (TIL) therapy and engineered TCR-based therapies. The Lifileucel TIL product, under FDA review, has demonstrated durable responses in heavily pre-treated metastatic melanoma patients, with overall response rates around 36%.

Additionally, CAR-T cell therapy, while facing challenges in solid tumors due to antigen escape and hostile TME, is being adapted for melanoma using novel targets such as GD2 and B7-H3. Dual CAR constructs and armored CARs co-expressing cytokines or checkpoint-resistant pathways may overcome these hurdles.

The immunotherapy revolution in melanoma continues to evolve, fueled by deeper understanding of tumor-immune interactions, refined biomarker strategies, and innovative therapeutic designs. While challenges such as resistance, toxicity, and patient heterogeneity persist, the integration of genomics, immunogenomics, and real-time monitoring tools promises a future of adaptive, patient-specific therapy.

As Dr. Jedd Wolchok, Chair of the Department of Medicine at MSKCC, stated, "We are entering an era where the immune system is no longer just a participant in cancer therapy — it is the architect of cure."