Metastatic Merkel cell carcinoma: tumor microenvironment, immunogenomics, and radiotherapy in the oncological approach

Abstract

Introduction: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high metastatic potential and poor prognosis in advanced stages (Valukas et al., 2026). The identification of Merkel cell polyomavirus (MCPyV) and the advent of immunotherapy have transformed the therapeutic paradigm. Objective: To synthesize evidence on the tumor microenvironment, immunogenomic profile, and role of radiotherapy in metastatic MCC through an exploratory systematic review with PICO questions. Methods: Exploratory systematic review following PRISMA 2020 (Page et al., 2021). Search in PubMed/MEDLINE, Europe PMC, and Scopus (January 2000 to October 2026). Studies on tumor microenvironment, genomic characterization, and radiotherapy in MCC were included. Results: Fifty-two records were identified; after screening, 10 studies were included. Tumor microenvironment analysis revealed significant differences between MCPyV-positive and negative MCC: virus-negative tumors exhibit higher mutational burden and UV signatures, while virus-positive tumors show increased CD8+ T cell infiltration and organized immune aggregates (Donizy et al., 2021; Haist et al., 2025). Short-course radiotherapy has demonstrated abscopal responses in anti-PD-1-resistant patients (Xu et al., 2018; Bloom et al., 2019). Conclusions: Metastatic MCC presents a heterogeneous immunogenic microenvironment conditioned by viral status. Radiotherapy emerges as a synergistic strategy with immunotherapy, with growing evidence of abscopal responses. Validated predictive biomarkers are required to optimize patient selection.