Abstract:

In recent years, immune checkpoint inhibitor (ICI) has led to substantial advances in the treatment of recurrent or metastatic advanced cutaneous melanoma (CM), significantly prolonging overall survival. However, due to the biological heterogeneity across melanoma subtypes, the degree of immune responsiveness varies considerably. In particular, acral melanoma (AM) (the predominant melanoma subtype in Asian populations, including China) has demonstrated limited benefit from ICI therapy, especially in the context of monotherapy. Currently, no systematic staging and standardized treatment guidelines are available for AM, and clinical evidence supporting the use of ICI in this rare subtype remains insufficient. In the neoadjuvant setting, several large phase Ⅱ/Ⅲ international trials in CM, including SWOG 1801 and NADINA, have shown that ICI-based neoadjuvant combination therapy significantly improves pathological response rates compared with traditional adjuvant approaches. Nevertheless, neoadjuvant treatment in AM remains in the exploratory stage. Early-phase clinical studies in resectable stage Ⅲ/Ⅳ AM suggest that toripalimab combined with intratumoral oncolytic virus therapy, or camrelizumab in combination with apatinib and temozolomide, may offer clinical benefit; however, confirmation of long-term survival benefit requires further validation in larger, prospective cohorts. In the adjuvant setting, for AM patients with BRAF mutations, real-world data from China have shown no significant difference in survival outcomes between dabrafenib plus trametinib and programmed death-1 (PD-1) inhibitor monotherapy in high-risk resectable stage Ⅲ/Ⅳ disease, although direct head-to-head comparisons are lacking. For patients with resectable stage Ⅲ/Ⅳ wild-type AM, combination adjuvant regimens incorporating PD-1 inhibitors may provide superior recurrence risk reduction and survival benefit compared to monotherapy. In the advanced disease setting, in Chinese populations, the objective response rates of PD-1 inhibitors such as pembrolizumab, toripalimab and penpulimab remain suboptimal in AM. ICI-based combination strategies (including those with chemotherapy, anti-angiogenic agents, dual or triple immune checkpoint blockade) may improve the immune microenvironment and clinical prognosis, but concerns regarding safety and tolerability persist. For patients with ICI-refractory AM, various novel approaches combining immunotherapy, targeted agents and chemotherapy are under investigation. Additionally, several next-generation immunotherapeutic modalities [including T-cell receptor-engineered (TCR-T) therapies, therapeutic cancer vaccines, chimeric antigen receptor T (CAR-T) cell therapy and antibody-drug conjugate (ADC)] are currently in development. This review aimed to provide a comprehensive overview of current clinical evidence on the use of ICI in acral melanoma across the neoadjuvant, adjuvant, and advanced disease settings. We highlighted the efficacy and safety of existing strategies, exploreed emerging combination regimens and predictive biomarkers, and discussed key areas for future research to inform clinical decision-making and optimize outcomes in this challenging melanoma subtype.

Key words: Acral melanoma, Immune checkpoint inhibitor, Neoadjuvant, Adjuvant, Combination therapy