Determinants of Resistance to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: A Narrative Review

BACKGROUND/AIM: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy frequently associated with Merkel cell polyomavirus (MCPyV) or ultraviolet (UV) mutagenesis. While immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis achieve response rates of 50-60%, primary and acquired resistance remain significant challenges. This review aims to synthesize current evidence on the determinants of ICI resistance in MCC to improve patient stratification and therapeutic strategies. MATERIALS AND METHODS: A comprehensive narrative review of scholarly literature was performed using SciSpace, Google Scholar, and PubMed databases. Studies focused on MCC pathogenesis, immunotherapy clinical trials, tumor microenvironment (TME) profiling, and molecular mechanisms of ICI resistance were analyzed. A total of 29 peer-reviewed sources were integrated to provide a multi-layered perspective on resistance. RESULTS: Resistance to ICIs in MCC is multifactorial, driven by TME heterogeneity, MHC-I down-regulation, T-cell exhaustion, and viral status-dependent immune recognition. "Cold" tumors lacking preexisting tissue-resident CD8+ and γδ T-cell circuits are predisposed to failure. Furthermore, tumor cell plasticity - shifting between neuroepithelial and mesenchymal-like states - actively shapes immune evasion. Emerging biomarkers such as circulating tumor DNA (ctDNA) and composite gene expression signatures show promise but require prospective validation. CONCLUSION: Understanding the interplay between viral status, genomic burden, and the immune landscape is essential for overcoming ICI resistance. Rational combination strategies, particularly ICI plus radiation or epigenetic modulators to restore MHC-I expression, offer pathways to improve outcomes in resistant disease.