肿瘤微环境（TME）在现有肝细胞癌（HCC）治疗效果有限的过程中发挥着至关重要的作用，肿瘤相关内皮细胞（TEC）作为TME的基本组成部分，极大地影响肿瘤进展和治疗效果。然而，TEC 在 HCC 中的确切作用和机制仍不清楚。我们采用多组学分析策略来研究 HCC 肿瘤微环境中 TEC 的单细胞和时空演化，显示出对免疫治疗的不同反应。通过对 HCC 患者临床队列的分析，我们探讨了 TEC 亚群与免疫治疗结果之间的相关性。通过全面的体外和体内研究证实了 TEC 亚群对免疫微环境的影响。为了进一步探讨不同 TEC 亚群在微环境调节中的机制及其对免疫治疗的影响，我们利用了 TEC 亚群特异性敲除小鼠模型以及人源化小鼠模型。在这项研究中，我们鉴定了一个新的 CXCL12 TEC 亚群，该亚群发挥着至关重要的作用HCC TME 中免疫抑制的作用。从功能上讲，CXCL12 TEC 通过分泌 CXCL12 阻碍 CD8 幼稚 T 细胞分化为 CD8 细胞毒性 T 细胞。此外，它们还吸引骨髓源性抑制细胞（MDSC）。开发了一种双特异性抗体，专门针对 CXCL12 和 PD1，在增强抗肿瘤免疫反应和推进 HCC 治疗方面显示出巨大的前景。CXCL12 TEC 在介导 HCC 微环境中的免疫抑制方面至关重要，靶向 CXCL12 TEC 提供了一种有前途的增强疗效的方法这项研究揭示了 HCC TME 中的一个关键机制，其中 CXCL12 TEC 成为免疫抑制的关键调节剂。 CXCL12 TEC 作为 CD8 初始 T 细胞激活抑制剂和 MDSC 招募剂的发现，显着促进了我们对 HCC 与免疫调节之间动态的理解。此外，精确靶向CXCL12和PD1的双特异性抗体的开发和应用已被证明可以增强人源化小鼠HCC模型中的免疫反应。这一发现强调了 HCC 的一个有前途的治疗方向，提供了扩大当前免疫疗法影响的潜力。版权所有 © 2024。由 Elsevier B.V. 出版。

The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood.We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of HCC patients, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models.In this research, we identified a new subset of CXCL12+ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12+ TECs impede the differentiation of CD8+ naïve T cells into CD8+ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy.CXCL12+ TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12+ TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients.This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12+ TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12+ TECs as inhibitors of CD8+ naïve T cell activation and recruiters of MDSCs significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.Copyright © 2024. Published by Elsevier B.V.