Clinical, Dermatoscopic, Histological and Molecular Prognostic and Predictive Factors of Metastatic Melanoma Response to Immunotherapy: A Systematic Review and Drug Class Meta-Analysis

<b>Introduction:</b> Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic melanoma; however, predictive markers of therapeutic response remain poorly defined. This study systematically assesses clinical, histological, and molecular predictors associated with survival outcomes in melanoma patients treated with ICIs. <b>Methods:</b> Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, a systematic search was conducted in MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between January 2018 and October 2025. Eligible studies reported associations between predictive factors and overall survival (OS) or progression-free survival (PFS) in adult melanoma patients receiving ICIs. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from univariate (UVA) and multivariate analyses (MVA) were synthesized using random-effects meta-analyses. <b>Results:</b> Sex was not a consistent predictor (contradictory effects; PFS heterogeneity I² ≈ 90%), whereas older age predicted worse OS (MVA continuous: HR 1.05, 95% CI 1.02-1.08; UVA ≥ 65 vs. <65: HR 1.70, 95% CI 1.36-2.12). Poor performance status, assessed using the Eastern Cooperative Oncology Group (ECOG) scale, strongly predicted inferior outcomes (ECOG ≥ 1 vs. 0: MVA OS HR 2.01, 95% CI 1.61-2.51; MVA PFS HR 1.49, 95% CI 1.18-1.88; ECOG ≥ 2 vs. <2: MVA OS HR 2.24, 95% CI 1.79-2.81). Elevated lactate dehydrogenase (LDH) was consistently associated with poorer survival (MVA OS HR 1.71, 95% CI 1.53-1.91; MVA PFS HR 1.61, 95% CI 1.41-1.85), whereas body mass index (BMI) > 25 kg/m² was associated with improved OS (HR 0.82, 95% CI 0.68-0.98). Higher disease burden predicted worse prognosis (Stage IV vs. III: MVA OS HR 1.57, 95% CI 1.16-2.13; >2 metastatic sites vs. ≤2: MVA OS HR 2.38, 95% CI 1.40-4.07; brain metastases: MVA OS HR 1.69, 95% CI 1.30-2.20; MVA PFS HR 1.52, 95% CI 1.00-2.33). Histologic and molecular factors showed prognostic value: ulceration worsened OS (UVA HR 2.08, 95% CI 1.25-3.44) and PFS (UVA HR 2.97, 95% CI 1.39-6.32); acral subtype had poorer OS than cutaneous melanoma (MVA HR 2.99, 95% CI 1.63-5.48); high tumor mutational burden (TMB) improved PFS (UVA HR 0.47, 95% CI 0.33-0.70); and cutaneous immune-related adverse events (irAEs) were associated with favorable outcomes (skin disorders: UVA OS HR 0.26, 95% CI 0.14-0.47; UVA PFS HR 0.50, 95% CI 0.34-0.74). In contrast, detectable circulating tumor DNA (ctDNA) predicted markedly worse PFS (MVA HR 4.72, 95% CI 2.31-9.65) and a non-significant trend toward worse OS (MVA HR 3.34, 95% CI 0.96-11.67). Liver metastases and programmed death-ligand 1 (PD-L1) expression were not significantly associated with survival. <b>Discussion:</b> This meta-analysis synthesizes evidence on clinicopathologic, laboratory, and histopathologic predictors of immunotherapy outcomes in metastatic melanoma. Performance status, age, LDH, BMI, and metastatic burden consistently correlated with prognosis, while ulceration, disease stage, and TMB emerged as key histologic determinants. Conversely, PD-L1 and gender showed no consistent predictive value, whereas cutaneous immune-related adverse events and ctDNA reflected favorable and poor outcomes, respectively. These findings highlight the multifactorial nature of immunotherapy response and support the further development of integrated prognostic models to refine patient stratification and optimize treatment outcomes.