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

## TL;DR

ABCB5 is a key molecule in melanoma that influences cancer cell resistance to treatment and tumor environment, making it a potential target for new therapies.

## Contribution

This review highlights ABCB5's role in melanoma progression, therapy resistance, and immune evasion, offering insights for future treatment strategies.

## Key findings

- ABCB5 promotes chemoresistance in melanoma stem-like cells through drug efflux mechanisms.
- ABCB5 contributes to an immunosuppressive tumor microenvironment by secreting cytokines and expressing PD-L1.
- ABCB5 is linked to pathways like PI3K/Akt and BCL-2, which are important for tumor survival and resistance.

## Abstract

Cutaneous melanoma is one of the most aggressive forms of skin cancer and remains difficult to treat due to its ability to adapt and develop resistance to therapy. Recent research suggests that a small subset of tumor cells with stem-like properties play an important role in disease progression and treatment failure. One molecule of growing interest is ABCB5, a membrane transporter associated with drug resistance, immune evasion, and tumor survival. This review summarizes current knowledge on how ABCB5 contributes to melanoma progression by influencing tumor cell plasticity and the surrounding tumor microenvironment. We discuss the biological mechanisms linked to ABCB5 expression, its potential value as a prognostic biomarker, and its relevance for future therapeutic strategies. A better understanding of ABCB5 may help guide the development of more effective and personalized treatment approaches for patients with 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.