Peritumoral Niche Predicts Response to Adjuvant Combination Therapy in Colorectal Liver Metastases

Adjuvant therapy (AT) improves outcomes for colorectal liver metastases (CRLM), yet predicting benefit, especially from adding targeted agents (Cetuximab or Bevacizumab) to chemotherapy, remains challenging. The spatial organization of the tumor microenvironment (TME) influences treatment response, yet its role in CRLM AT efficacy is unclear. We performed imaging mass cytometry (IMC) on 311 regions across tumor core, invasive margin, and peritumor (PT) tissues from 35 AT-treated CRLM patients. Systematic spatial proteomic analysis revealed distinct cholangiocyte-anchored niches within the PT region associated with recurrence-free survival (RFS): an "Immune-Rich" (PIR-Niche) enriched with B cells and CD8+ T cells, and a "Stromal-Metabolic" (PSM-Niche) dominated by CD163+ macrophages and Collagen-I+ stromal cells. The Immune-Stromal Ratio (ISR), a metric quantifying the relative abundance of these two niches, predicted RFS specifically in patients receiving combination therapy (p=0.044). To enhance clinical applicability, we developed SpMap, a deep learning tool inferring the ISR from routine H&E slides. The SpMap-derived ISR significantly predicted RFS in discovery (p=0.036) and independent test (n=95, p=0.023) cohorts, identifying high-ISR patients deriving significant benefit from combination therapy. Integrated spatial and single-cell transcriptomics confirmed distinct cellular compositions and revealed enrichment of angiogenesis pathways in PIR-Niches and mTORC1 signaling in PSM-Niches. Our work explores the spatial architecture within peritumor, captured by the ISR, as a potential predictor of adjuvant combination therapy response in CRLM. Furthermore, SpMap provides a H&E-based tool for patient stratification, while uncovering potential targetable pathways driving niche function.辅助治疗（Adjuvant therapy, AT）可改善结直肠癌肝转移（colorectal liver metastases, CRLM）患者的预后，但准确预测其治疗获益——尤其是在化疗基础上联用西妥昔单抗（Cetuximab）或贝伐珠单抗（Bevacizumab）这类靶向药物时——仍极具挑战。肿瘤微环境（tumor microenvironment, TME）的空间组织特征会影响治疗响应，但该特征在CRLM辅助治疗疗效中的作用尚不明确。本研究对35例接受辅助治疗的CRLM患者的肿瘤核心、侵袭边缘及瘤周（peritumor, PT）组织共311个区域开展成像质谱流式（imaging mass cytometry, IMC）分析。系统性空间蛋白质组学分析显示，瘤周区域内存在与无复发生存期（recurrence-free survival, RFS）显著相关的两类胆管细胞锚定生态位：一类是以B细胞与CD8+ T细胞富集为特征的免疫富集型（PIR-Niche），另一类是以CD163+巨噬细胞及I型胶原阳性基质细胞为主导的基质代谢型（PSM-Niche）。免疫基质比（Immune-Stromal Ratio, ISR）——用于量化这两类生态位相对丰度的指标——可特异性预测接受联合治疗患者的无复发生存期（p=0.044）。为提升临床应用潜力，本研究开发了SpMap：一款可从常规苏木精-伊红（H&E）切片中推导ISR的深度学习工具。经SpMap推导得到的ISR可在发现队列（p=0.036）及独立验证队列（n=95, p=0.023）中有效预测无复发生存期，并可识别出能从联合治疗中获得显著获益的高ISR患者群体。整合空间转录组与单细胞转录组分析证实，两类生态位的细胞组成存在显著差异，且免疫富集型生态位（PIR-Niche）富集血管生成通路，基质代谢型生态位（PSM-Niche）则富集mTORC1信号通路。本研究揭示了瘤周区域的空间结构特征（通过ISR量化）可作为CRLM患者辅助联合治疗响应的潜在预测标志物。此外，SpMap提供了一种基于H&E切片的患者分层工具，同时也阐明了调控生态位功能的潜在可靶向通路。