空间酸相关生态位为结直肠癌肝转移中基于伊立替康的DEB-TACE提供信息：一项多中心随机试验。
完整摘要 · 中文译文
背景与目的：药物洗脱微球经动脉化疗栓塞（DEB-TACE），尤其是基于伊立替康的方案，已成为不可切除结直肠癌肝转移（CRLM）的肝脏导向治疗选择，然而转移微环境生物学与局部药物递送之间的关系仍不明确。 方法：我们整合了批量、单细胞和空间转录组学与空间药物基因组学推断（SpaDR），以表征CRLM中的酸相关状态并预测区域药物敏感性，比较了UniPearls和HepaSphere微球的pH依赖性伊立替康释放，并在四项中心随机试验中对35例不可切除CRLM患者评估了两种平台。 结果：CRLM表现出酸相关转录表型（AcidScore），部分与TACE无应答肝细胞癌共享，并与CRLM较短的总生存期相关。该表型定位于SPP1+巨噬细胞和癌相关成纤维细胞的空间组织生态位，其中AcidScore和恶性上皮随距血管距离增加而升高，与推测的基质-代谢屏障一致。SpaDR在大多数切片中将较高的AcidScore与较低的预测SN-38 IC50相关联，识别出该界面之外的候选敏感性。据此，UniPearls在所有测试pH下24小时内释放的伊立替康均多于HepaSphere，pH 5.7时差异最大。最终DEB-TACE后的疾病控制率UniPearls更高（符合方案集，100% vs. 68.75%；p = 0.018），最终技术成功率亦更高（100% vs. 76.47%；p = 0.046）；客观r 缓解率和不良事件发生率相似。非劣效性在各项敏感性分析中均成立，而优效性则对缺失结局假设敏感。 结论：酸相关空间组织与药物反应预测为CRLM局部伊立替康给药提供了依据。这些发现支持进一步评估基于UniPearls的DEB-TACE以及将生态位生物学与临床获益联系起来的前瞻性生物标志物分层研究。 试验注册：NCT06021015。注册日期2023年8月27日，https://clinicaltrials.gov/study/NCT06021015。 本研究识别了结直肠肝转移中酸相关的细胞组织以及预测对伊立替康活性代谢物敏感性较高的区域。在酸性实验室条件下，UniPearls释放的伊立替康多于HepaSphere，一项小型多中心随机试验的初步证据显示其短期疾病控制率更高。这些发现促使进一步研究酸相关肿瘤特征如何影响局部伊立替康暴露和治疗反应。
完整摘要 · 英文原文
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. This study identified acid‐associated cellular organization in colorectal liver metastases and regions with greater predicted sensitivity to irinotecan's active metabolite. UniPearls released more irinotecan than HepaSphere under acidic laboratory conditions, with preliminary evidence of higher short‐term disease control in a small multicentre randomised trial. These findings motivate further investigation of how acid‐associated tumour features may influence local irinotecan exposure and treatment response.