An Innervated and Vascularized HNSCC-on-a-Chip Model Built on Defined and Tunable Engineered Extracellular Matrices

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Abstract Understanding the tumor microenvironment (TME) requires experimental platforms that faithfully recapitulate its key components. Here, we present an innervated and vascularized head and neck squamous cell carcinoma (HNSCC)-on-a-chip platform built with fully defined and tunable engineered extracellular matrices (eECMs). In a stepwise increase of complexity, we first co-cultured patient-derived HNSCC cells, cancer-associated fibroblasts, and endothelial cells within tailored eECMs, revealing matrix-dependent differences in self-organization and chemotherapeutic sensitivity. We then integrated these 3D constructs into a cancer–vasculature-interface, which enabled analysis of eECM-dependent directional collective migration and metastatization. Finally, we incorporated HNSCC-specific innervation through injectable 3D human bioengineered trigeminal ganglia, establishing a chip-based innervation–tumor–vasculature tri-interface. Together, this all-human platform captures fundamental determinants of HNSCC progression, including a fully defined ECM, vasculature, and innervation, within a single modular system that is broadly adaptable for interrogating how the tumor microenvironment shapes solid tumor behavior and therapeutic responses. Teaser HNSCC-on-a-chip integrates defined ECM, vasculature, and innervation to investigate tumor behavior and therapeutic responses.

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