Liver Int. 2026 Dec;46(12):e70931. doi: 10.1111/liv.70931.
ABSTRACT
BACKGROUND & AIMS: Drug-eluting bead transarterial chemoembolisation (DEB-TACE), particularly irinotecan-based regimens, has emerged as a liver-directed option for unresectable colorectal liver metastases (CRLM), yet how metastatic-niche biology relates to local drug delivery remains poorly defined.
METHODS: We integrated bulk, single-cell, and spatial transcriptomics with spatial pharmacogenomic inference (SpaDR) to characterize acid-associated states in CRLM and predict regional drug sensitivity, compared pH-dependent irinotecan release of UniPearls and HepaSphere microspheres, and evaluated both platforms in a four-centre randomised trial of 35 patients with unresectable CRLM.
RESULTS: CRLM exhibited an acid-associated transcriptional phenotype (AcidScore), partly shared with TACE-nonresponder hepatocellular carcinoma and associated with shorter overall survival in CRLM. This phenotype localized to a spatially organized niche of SPP1+ macrophages and cancer-associated fibroblasts, in which AcidScore and malignant epithelium increased with distance from the vasculature, consistent with a putative stromal-metabolic barrier. SpaDR linked higher AcidScore to lower predicted SN-38 IC50 in most sections, identifying candidate sensitivity beyond this interface. Accordingly, UniPearls released more irinotecan than HepaSphere within 24 h at every pH tested, with the largest difference at pH 5.7. Disease control after the final DEB-TACE was higher with UniPearls (per-protocol, 100% vs. 68.75%; p = 0.018), as was final technical success (100% vs. 76.47%; p = 0.046); objective response and adverse-event frequencies were similar. Non-inferiority held across sensitivity analyses, whereas superiority was sensitive to missing-outcome assumptions.
CONCLUSIONS: Acid-associated spatial organization and drug-response predictions provide a rationale for local irinotecan delivery in CRLM. These findings support further evaluation of UniPearls-based DEB-TACE and prospective biomarker-stratified studies linking niche biology to clinical benefit.
TRIAL REGISTRATION: NCT06021015. Registered 27 August 2023, https://clinicaltrials.gov/study/NCT06021015.
PMID:42969685 | DOI:10.1111/liv.70931
