Sha Bowen, Tong Fei, Shu Qinghua, Wu Miao, Zhao Liang, Zhang Yufeng
Department of Hepatopancreatobiliary Surgery, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210003, Jiangsu, China.
Department of Hepatobiliary Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou, 225200, Jiangsu Province, China.
Sci Rep. 2025 Jul 2;15(1):23501. doi: 10.1038/s41598-025-08602-1.
Immunogenic cell death (ICD) is crucial for cancer development and enhances the effectiveness of immunotherapy by triggering an adaptive immune response. However, the impact of ICD-related genes (ICDRGs) on iCCA progression and patient prognosis remains unclear. iCCA samples from The Cancer Genome Atlas (TCGA) were categorized into two ICD-associated subtypes by consensus clustering, and patient prognosis in these subgroups was assessed. Single-cell RNA sequencing was conducted on viable cells from 8 iCCA patients to understand their transcriptomic profiles, heterogeneity, and immune microenvironment. Principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) analysis were applied to identified 13 cell subpopulations. The gene set enrichment analysis (GSEA) was used to investigate pathway heterogeneity among these subpopulations. CellChat was employed for intercellular communication analysis. Pseudotime trajectory analyses with CytoTRACE and Monocle2 were used to explore differentiation trajectories and functional differences across various states. 30,485 single cells from human iCCA and normal tissues were sequenced, revealing two ICD-associated subtypes. The ICD-low subtype correlates with better clinical outcomes, whereas the ICD-high subtype is linked to increased immune cell infiltration and immune response signaling activity. Distinct biological functions and metabolic characteristics were observed in iCCA between high- and low-ICD groups. High infiltration of ICD-low subtype in iCCA is associated with poor prognosis, potentially through the ANXA-FPR pathway affecting macrophage proliferation and differentiation. Our study constructed an immunogenic cell death-related signature that can promise prognosis prediction and personalized medicine in iCCA. This finding might help guide clinicians for iCCA patients.
免疫原性细胞死亡（ICD）对癌症发展至关重要，并通过触发适应性免疫反应提高免疫治疗的效果。然而，ICD相关基因（ICDRGs）对肝内胆管癌（iCCA）进展和患者预后的影响仍不清楚。通过一致性聚类将来自癌症基因组图谱（TCGA）的iCCA样本分为两种与ICD相关的亚型，并评估这些亚组中的患者预后。对8例iCCA患者的活细胞进行单细胞RNA测序，以了解其转录组谱、异质性和免疫微环境。应用主成分分析（PCA）和均匀流形近似与投影（UMAP）分析来识别13个细胞亚群。基因集富集分析（GSEA）用于研究这些亚群之间的通路异质性。使用CellChat进行细胞间通讯分析。使用CytoTRACE和Monocle2进行伪时间轨迹分析，以探索不同状态下的分化轨迹和功能差异。对来自人类iCCA和正常组织的30485个单细胞进行测序，揭示了两种与ICD相关的亚型。ICD低亚型与更好的临床结果相关，而ICD高亚型与免疫细胞浸润增加和免疫反应信号活性增加有关。在高ICD组和低ICD组的iCCA中观察到不同的生物学功能和代谢特征。iCCA中ICD低亚型的高浸润与预后不良相关，可能是通过膜联蛋白-FPR途径影响巨噬细胞的增殖和分化。我们的研究构建了一个与免疫原性细胞死亡相关的特征，可用于iCCA的预后预测和个性化医疗。这一发现可能有助于指导iCCA患者的临床治疗。
