Checkpoint Inhibitors and Beyond: A Systematic Review of Immunotherapy in Cutaneous Malignancies

Skin cancers represent a major health concern, and there is a need for more effective treatment approaches, among which immune checkpoint inhibitors have become a particularly important recent development. This study aimed to explore the efficacy and tolerability of immune checkpoint inhibitors, intratumoral immunotherapies, targeted agents, and their combinations in advanced cutaneous malignancies. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-conform review of PubMed (2012-2024) identified 26 studies, including randomized trials, observational cohorts, network meta-analyses, and systematic reviews, evaluating checkpoint inhibitors, anti-PD-1/PD-L1and anti-CTLA-4. Outcomes included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), biomarkers, and treatment-related adverse events. This meta-analysis of 26 studies (2012-2024) evaluated treatments for cutaneous malignancies, including melanoma, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), covering systemic immunotherapies (PD-1, CTLA-4), combination checkpoint inhibitors, and novel approaches like IL-12 electroporation. Melanoma: PD-1 therapies showed durable benefits; ipilimumab retreatment yielded 42% two-year survival. MCC: Avelumab achieved a median OS of 12.9 months. cSCC: Nivolumab PFS 8.2 months; cemiplimab 12-month PFS >53%. Targeted therapy: BRAF/MEK inhibitors reached OS ~33 months. Emerging strategies: TIL-based and neoadjuvant immunotherapy showed high pathological and durable responses. Overall, combination therapies consistently outperformed monotherapies in survival and response. Adverse events were common, especially with combination therapy, with severe immune-related toxicities reported in 30-59% of cases, while monotherapies were generally safer. Overall, immunotherapy offers substantial, often long-lasting benefits, though careful patient selection and monitoring are essential to balance efficacy and toxicity. Combination immunotherapies and targeted regimens are more effective for advanced melanoma, although they have increased toxicity.