The Immune Landscape of Acral Melanoma: From Basic to Clinical

BACKGROUND: Acral melanoma (AM) is an aggressive melanoma subtype with poor prognosis and limited response to immune checkpoint inhibitors (ICIs). Despite increasing research efforts, the mechanisms underlying therapeutic resistance remain incompletely understood. AIM: This review examines the mechanisms driving immunotherapy resistance in AM, summarizes current clinical advances in combination regimens, and explores future therapeutic directions. METHODS: A narrative review of recent literature was undertaken, encompassing studies on resistance mechanisms and clinical trials investigating novel ICI-based combination therapies for AM. RESULTS: AM exhibits distinct immunosuppressive microenvironment characterized by low tumor mutational burden, reduced CD8+ T-cell infiltration, enrichment of regulatory T cells, and specific genetic alterations. Emerging clinical data demonstrate that combination regimens-particularly dual ICIs (anti-PD-1 plus anti-CTLA-4) and ICI combinations with anti-angiogenic agents or chemotherapy-have shown promising efficacy, with some achieving superior response rates in AM patients. DISCUSSION: Understanding resistance mechanisms is critical for identifying novel therapeutic targets and optimizing personalized strategies. Current evidence suggests combination therapies may overcome resistance and improve outcomes, though optimal regimens and sequencing require further investigation. CONCLUSION: Continued research into innovative combination approaches and predictive biomarkers is urgently needed to improve survival in AM.