Antonio Di Guardo, Federica Trovato, Carmen Cantisani, Francesco Ricci, Giovanni Di Lella, Francesco Moro, Roberto Morese, Annarita Panebianco, Steven P. Nisticò, Giovanni Pellacani, Luca Fania
Advanced cutaneous squamous cell carcinoma (aCSCC) comprises locally advanced and metastatic disease not amenable to curative surgery or radiotherapy and is associated with substantial morbidity, mortality, and healthcare costs. This narrative review summarizes current knowledge on the epidemiology, biology, clinical presentation, and staging of aCSCC and critically appraises therapeutic strategies with a focus on programmed death 1 (PD-1) blockade. Immune checkpoint inhibitors now represent the main systemic treatment for advanced cSCC, with clinical trials and observational studies reporting response rates around 45-60%, sustained benefit in a subset of patients, and a manageable yet clinically relevant profile of immune-related toxicities. However, outcomes remain heterogeneous, particularly in elderly, comorbid, and immunosuppressed patients. We therefore review established and emerging prognostic determinants spanning clinical, anatomical, histopathological, metabolic, inflammatory, and on-treatment domains. Priorities for biomarker-enriched studies and harmonized real-world registries to enable more refined risk stratification and genuinely personalized, multidisciplinary management of aCSCC are also outlined.