Resolving melanoma heterogeneity at single-cell resolution: implications for target discovery and therapy resistance

Melanoma is characterized by profound intra-tumoural heterogeneity and a complex tumour microenvironment (TME), which are primary drivers of therapy resistance. Conventional bulk sequencing lacks the resolution to capture these cellular nuances. Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) and spatial multiomics, have fundamentally advanced our understanding of melanoma by enabling high-resolution characterization of malignant cell states, immune ecosystems and tumour microenvironment interactions. In this review, we summarize recent advances in single-cell multiomics studies of melanoma heterogeneity and therapy resistance, focusing on the identification of drug-tolerant persister states, immune escape mechanisms and resistance-associated cellular transitions. We further discuss how single-cell approaches facilitate target discovery, biomarker development and the rational design of combination therapies. By integrating multiomics profiling, computational modelling and pharmacological validation, these technologies provide a framework for translating cellular-level insights into precision therapeutic strategies. Finally, we highlight current challenges and future opportunities for clinical implementation of single-cell-guided approaches in refractory melanoma.