Immunotherapy in Merkel Cell Carcinoma of the Skin: A 2025 Comprehensive Review

Purpose: Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. Although immunotherapy has transformed MCC management, published data remain limited. This comprehensive review evaluates current evidence on immunotherapy in MCC. Methods: Peer-reviewed articles published between 2000 and 2024 were manually searched in four databases: Scopus, ScienceDirect, PubMed and MEDLINE, using the keywords “Merkel cell carcinoma” AND “immunotherapy”. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology was employed. Results: Immunotherapy can be given in different settings: (A) Neoadjuvant: The CheckMate 358 trial reported a 54.5% response rate among 33 radiologically evaluable patients treated with nivolumab, each showing over 30% tumor reduction. (B) Adjuvant: (1) The ADMEC-O phase II trial demonstrated improved disease-free survival with adjuvant nivolumab. (2) The ADAM phase III trial evaluates adjuvant avelumab in node-positive patients post-surgery/radiation, with common side effects including nausea, fatigue, and itching. (3) STAMP, a phase III trial, investigates pembrolizumab in stage I–III MCC. Both ADAM and STAMP have completed accrual, pending results. (C) Primary therapy: KEYNOTE-017 and JAVELIN trials reported a 60% overall response rate and ~40% 3-year progression-free survival with first-line pembrolizumab or avelumab. Both agents also show promise as salvage therapies. Conclusion: Immunotherapy demonstrates encouraging outcomes in MCC across various treatment stages. Continued research is essential to optimize timing, integrate with multimodal therapies, and address resistance mechanisms such as intra-tumoral STING activation and tumor-associated macrophages.