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.