The application of 3D cell culture for melanoma in vitro models

Melanoma remains a formidable clinical challenge due to its high metastatic potential and resistance to conventional therapies, in part reflecting the failure of two-dimensional (2D) culture systems to recapitulate the complex tumor microenvironment (TME). Three-dimensional (3D) cell culture models have emerged as superior platforms over traditional 2D systems for recapitulating the complex TME of melanoma, including native extracellular matrix (ECM) architecture, cell-cell interactions, and biochemical gradients essential for accurate drug screening and mechanistic studies. In this review, we conducted a comprehensive literature survey to classify and critically evaluate melanoma 3D culture platforms into five categories, including melanoma spheroids, biomaterial-encapsulation cultures, melanoma skin equivalents, melanoma-on-chip, and bio-printed melanoma model, focusing on biomaterial composition, architectural fidelity, mechanical properties, and cellular integration, and systematically comparing their advantages and disadvantages. These models have advanced our understanding of melanoma progression, drug resistance mechanisms, cellular behavior, and they offer more reliable platforms for drug screening and development of personalized therapies. Although numerous challenges still need to be tackled, like the current biomaterials seldom replicate the distinct ECM of different skin layers and often neglect the incorporation of immune cells and adipocytes, emerging technologies hold promises for overcoming these challenges by enabling precise fabrication of tissue complexity, incorporation of vasculature, and integration of immune components. These innovations are poised to enhance the physiological relevance of melanoma models, ultimately facilitating the development of more effective treatments and improving patient outcomes. STATEMENT OF SIGNIFICANCE: Melanoma remains a formidable clinical challenge due to its high metastatic potential and resistance to conventional therapies. 3D cell culture models have emerged as superior platforms over traditional 2D systems for recapitulating the complex TME of melanoma. In this review, we classified melanoma 3D cell culture models into five categories, including melanoma spheroids, biomaterial-encapsulation cultures, melanoma skin equivalents, melanoma-on-chip, and bio-printed melanoma model, focusing on biomaterial composition, architectural fidelity, mechanical properties, and cellular integration, and systematically comparing their benefits and costs. In addition, we also highlighted the challenges of the development on melanoma 3D culture platforms for drug screening and mechanistic studies and discussed the future perspective on the development on melanoma 3D culture platforms.