Micropharmacology beyond Target Expression: Mapping Barriers to Intratumoral Drug Delivery

High-dimension spatial technologies are broadly being used to map the cellular and molecular organization of human cancers including tumor antigens and drug targets. This has revealed extensive spatial heterogeneity of target proteins but does not quantify drug distribution itself. Exposing additional complexities for drug targeting and delivery, Lu and colleagues recently applied highly multiplexed spatial proteomics to tumors from patients treated with fluorescently labeled antibody therapeutics. Quantifying drug penetration and distribution on cells of specific phenotypes, this approach identified compounding challenges that would limit therapeutic success as both target and therapeutic distribution are highly variable between patients and within individual tumors. Macrophage uptake, stromal barriers, vascularization differences, and epithelial permeability were all associated with altered antibody distribution. As expected, highly desmoplastic pancreatic cancers had poor drug delivery, and similar fibroblast- and extracellular matrix–rich microenvironments were also identified in head and neck squamous cell carcinomas as broadly prevalent barriers to drug delivery. Providing a measurement strategy for single-cell drug distribution, this work points toward opportunities to predict these barriers in precision medicine and design drugs that overcome them as a clinically impactful frontier.