In this study, we show for the first time that heterogeneous heterocellular 3D models of PDAC and HNSCC can be more effectively destroyed using triple-receptor-targeted TR-PINs (EGFR-, HER-2-, and TfR-specific) that would otherwise partially evade single-receptor EGFR-targeted PDT. This evidence concerns the gene ERBB2 and head and neck squamous cell carcinoma.