ABCB5: A Key Regulator Linking Stem Cell Plasticity, Tumor Microenvironment, and Therapy Resistance in Cutaneous Melanoma

Cutaneous melanoma is one of the most aggressive skin cancers. Over the years, multiple studies have focused on identifying novel treatment strategies, with increasing attention directed toward immune-modulating mechanisms within the tumor microenvironment. Among these, ATP-binding cassette transporters and stem-associated pathways have been shown to influence drug response and immune escape. ABCB5 is a gene with multiple isoforms that significantly influences the immune response. In melanoma, the ABCB5α isoform is predominantly expressed, particularly in tumor stem-like cells where it promotes chemoresistance through active drug efflux. ABCB5 has also been linked to the regulation of PI3K/Akt, BCL-2, and miR-145-associated pathways. Moreover, ABCB5-positive cells contribute to the formation of an immunosuppressive microenvironment by secreting cytokines (IL-6, IL-8, TGF-β) and expressing immune checkpoint ligands, such as PD-L1, thereby favoring tumor progression and a poor prognosis. This review integrates current data on the molecular and microenvironmental mechanisms underlying melanoma progression and therapy resistance, and positions ABCB5 within the broader landscape of melanoma resistance mechanisms, emphasizing both its potential and its current limitations as a biomarker and therapeutic target.