Molecular Drivers of Progression and Therapy Resistance in Cutaneous Melanoma

Cutaneous melanoma is one of the most aggressive skin cancers known. Over the years, multiple studies have focused on researching novel treatment options. For this purpose, numerous areas have been analyzed, and the focus has shifted toward the mechanisms by which immune-modulating molecules act within the microenviron-ment. 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 melano-ma, the ABCB5α isoform is predominantly expressed, primarily in tumor stem-like cells. Thus, it can alter the effects of medications by promoting chemoresistance via ac-tive drug efflux. The gene also regulates pathways PI3K/Akt, BCL-2, and miR-145, leading to overexpression. ABCB5 positive cells create an immunosuppressive micro-environment via cytokines (IL-8, IL-6, TGF-β) and death ligands (PD-L1), favoring tumor progression, thus correlating with poor prognosis. This review integrates cur-rent data on the molecular and microenvironmental mechanisms, underlying mela-noma progression and therapy resistance, highlighting ABCB5 as one of the several emerging biomarkers with potential prognostic and therapeutic relevance.