Developing effective treatments for malignant melanoma remains a complex challenge, requiring models that accurately replicate the tumor microenvironment to study metastasis and drug response. Whereas in vitro models have become essential tools due to their tunability and controllability, systems incorporating both biomimetic extracellular matrices (ECM) and vascular components are more complex and therefore remain challenging. In this study, we present an in vitro melanoma model comprising a dermal decellularized ECM (dECM) together with both blood and lymphatic vessels, cultured within a commercial microfluidic platform that enables high-throughput testing. Our system features a triculture melanoma spheroid embedded within a dermis dECM hydrogel and flanked by vascular structures, effectively recreating key aspects of the melanoma microenvironment, as confirmed by immunostaining for canonical markers and morphological resemblance. Proof-of-concept drug testing demonstrates the model’s suitability for high-throughput drug screening, as validated by cytotoxicity assays. The complexity and biomimetic nature of this model provides a robust platform for studying melanoma progression, tumor-vascular interactions, and therapeutic responses, ultimately offering a promising alternative for in vitro melanoma research and drug development.

DOI: 10.1021/acsabm.5c02329