Spatial Acid‐Associated Niches Inform Irinotecan‐Based DEB ‐ TACE in Colorectal Liver Metastases: A Multicentre Randomized Trial

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 IC 50 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