Tumor Mutational Burden as a Predictive Biomarker for Immunotherapy Response in Acral Melanoma: A Comprehensive Molecular and Clinical Analysis

Acral melanoma, a rare yet aggressive subtype of cutaneous melanoma, exhibits distinct genomic and clinical characteristics compared to non-acral counterparts. Despite advancements in immune checkpoint inhibitor (ICI) therapy, predictive biomarkers for treatment response remain incompletely elucidated. Tumor mutational burden (TMB), a quantifiable measure of somatic mutations within the tumor genome, has emerged as a potential biomarker for immunotherapy efficacy across various malignancies. This review critically evaluates the role of TMB in predicting clinical outcomes to ICIs in acral melanoma, integrating evidence from molecular profiling studies and clinical trials. We discuss the interplay between TMB, tumor microenvironment (TME), and immune evasion mechanisms, while addressing limitations such as heterogeneity in TMB quantification and confounding factors like ultraviolet (UV) signature mutational patterns. Our analysis underscores the need for standardized TMB thresholds and multimodal biomarker approaches to optimize patient stratification in this challenging disease subset.