Neoadjuvant Immunotherapy Strategies in Stage III Melanoma

Stage III melanoma carries a high risk of regional relapse and distant metastasis despite complete surgical resection. Neoadjuvant immunotherapy—administered prior to definitive surgery—aims to reduce tumour burden, eradicate micrometastatic disease and provide early systemic immune engagement. By exposing the intact tumour to immune checkpoint inhibitors, this approach can induce robust T-cell infiltration, generate immunological memory and enable in vivo assessment of treatment response. Key strategies include monotherapy with anti-PD-1 agents, dual checkpoint blockade combining anti-PD-1 with anti-CTLA-4, and emerging combinations targeting alternative checkpoints or epigenetic modulators. Pathological response rates, particularly complete eradication of viable tumour cells, correlate strongly with long-term recurrence-free survival and may serve as surrogate endpoints. Integration of molecular and immune biomarkers—such as interferon-γ signatures, T-cell clonality and tumour-infiltrating lymphocyte density—promises to personalise neoadjuvant regimens, optimise patient selection and mitigate treatment-related toxicity. Globally, these advances herald a shift towards precision immunotherapy in operable high-risk melanoma, improving outcomes and informing strategies across other solid malignancies.

Research from Nature Portfolio

Recent studies have demonstrated that combining LAG-3 blockade with PD-1 inhibition prior to surgery yields high rates of pathological complete response (pCR) in resectable stage III melanoma. In a phase II trial, patients received two neoadjuvant doses of the LAG-3 antibody relatlimab plus nivolumab, followed by surgical resection and adjuvant therapy. The regimen achieved a pCR rate exceeding 50 %, with over 90 % overall pathological response and excellent short-term recurrence-free survival. Treatment was well tolerated with no grade 3–4 immune-related adverse events in the preoperative setting. Translational analyses revealed that baseline immune cell infiltration and a decrease in immunosuppressive M2 macrophages during therapy were associated with response. These findings validate dual-checkpoint inhibition as an efficacious and safe neoadjuvant strategy and support further evaluation in larger randomised studies.

Neoadjuvant Immunotherapy Strategies in Stage III Melanoma publication trend

The graph below shows the total number of articles in neoadjuvant immunotherapy strategies in stage iii melanoma across all publications each year (not limited to Nature Index journals).

Technical terms

Neoadjuvant therapy: Treatment given before the main intervention (surgery) to shrink a tumour or address micrometastases.

Immune checkpoint inhibitor: A drug that blocks inhibitory pathways in T cells (e.g. PD-1, CTLA-4) to enhance anti-tumour immunity.

Pathological complete response (pCR): Absence of viable cancer cells in resected tissue after neoadjuvant therapy, indicating maximal tumour regression.

PD-1 (programmed cell death protein 1): An inhibitory receptor on T cells that, when engaged, dampens immune responses.

CTLA-4 (cytotoxic T-lymphocyte-associated protein 4): An immune checkpoint molecule that regulates early T-cell activation.

Biomarker: A measurable indicator (molecular, cellular) used to predict therapeutic response or prognosis.

Tumour microenvironment: The complex network of cancer cells, immune cells, stromal cells and signalling molecules within and around a tumour.

References

1. Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials ☆. Annals of Oncology (2023).
2. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature (2022).
3. Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma. Annals of Oncology (2021).
4. IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma. Journal of Experimental Medicine (2023).
5. Neoadjuvant Immunotherapy: A Promising New Standard of Care. International Journal of Molecular Sciences (2023).