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Single-cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human solid tumors

ABSTRACT: The development of effective antibody therapeutics has been hampered by a lack of methods to measure drug delivery and activity within tumors at single-cell resolution. Here we introduce single-cell spatial pharmacobiology (SSP), an analytical framework that integrates in situ imaging of a systemically infused, fluorescently labeled therapeutic antibody with high-plex spatial proteomics to quantify antibody distribution, target engagement, and tumor microenvironment (TME) architecture. We applied SSP to tumor tissues from patients with head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma who had received the antibody panitumumab-IRDye800 in phase I trials. SSP identified pronounced spatial heterogeneity in single-cell drug delivery and target engagement, shaped by conserved stromal barriers, including periostin-rich extracellular matrix assemblies and fibroblast activation protein⁺ cancer-associated fibroblast neighborhoods, which were associated with reduced antibody delivery in both tumor types. SSP measures drug-target–TME interactions in human tumors and can support studies of resistance mechanisms, dosing strategies, and discovery of spatial biomarkers for precision oncology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249198 | GEO | 2026/03/31

REPOSITORIES: GEO

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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.

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Single-cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human solid tumors

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