Neoadjuvant Immunotherapy in Cutaneous Squamous Cell Carcinoma: Systematic Literature Review and State of the Art

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer with increasing incidence worldwide. High-risk cSCCs often require extensive surgical treatments, which can impair anatomical function and aesthetics. Neoadjuvant immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as cemiplimab and pembrolizumab, has emerged as a promising approach to enhance tumor control and surgical outcomes. We performed a systematic review to evaluate the efficacy and safety of neoadjuvant immunotherapy in high-risk cSCC. Methods: A systematic review and proportional meta-analysis focusing on neoadjuvant immunotherapy for cSCC were conducted following PRISMA guidelines. MEDLINE and Scopus databases were searched up to September 2024 using predefined terms. Recorded findings were pathological/radiological response, 1-year disease-free survival (DFS), and overall survival (OS). Data extraction and risk-of-bias assessment were independently performed by two reviewers. Statistical analysis included fixed- and random-effects models, with heterogeneity assessed using Cochran’s Q statistic and the I² index. Results: Nine studies met the inclusion criteria. The pooled pathologic response rate was 72.2% (95% CI: 57.7–84.6), and the radiological response rate was 54.8% (95% CI: 38.6–70.5), with moderate heterogeneity. Pooled 1-year DFS and OS proportions were 91.1% (95% CI: 85.0–95.3) and 90.6% (95% CI: 85.1–95.0), respectively, demonstrating homogeneity across studies. Adverse events were consistent with previously reported immune-related toxicities, with rare severe events. Conclusions: Neoadjuvant immunotherapy is a promising therapeutic strategy for high-risk cSCC, with high pathologic response rates and high survival outcomes. However, standardization of treatment protocols and further trials are needed to optimize efficacy, ensure safety, and assess long-term benefits.