On July 11, 2024, the Zhang Lab from the Biomedical Pioneering Innovation Center (BIOPIC)at Peking University, published a paper entitled “Pan-cancer integrative analyses dissect the remodeling of endothelial cells in human cancers” in National Science Review. This study integrated public single-cell RNA-seq data of 575 cancer patients from 19 solid tumor types,systematically revealing the compositional and functional heterogeneity of tumor endothelial cells. It provided an in-depth analysis of the functional state transitions of tumor endothelial cells from the perspectives of different tissues and cancer types. Importantly, this study highlightedCXCR4+ tip cells and SELE+ veins as representative pro-angiogenic and pro-inflammatory phenotypes, respectively, elucidating their different associations with responses to anti-angiogenic therapy and immune checkpoint therapy. Theseintegrative resources and findings provide new insights for precise interventions in the tumor vascular system (Figure 1).

　　Figure 1. Key findings of the pan-cancer human endothelial cell atlas

　　In recent years, tumor immunotherapy has achieved remarkable success. Previous research by Academician Zemin Zhang’s team has revealed the heterogeneity of various immune cells across different cancer types and their close association with therapeutic responses. Non-immune cells in the tumor microenvironment, particularly endothelial cells, play crucial roles in tumor initiation, progression, and metastasis. Currently, anti-angiogenic therapies mainly target tumor endothelial cells to inhibit neovascularization, thereby limiting the supply of oxygen and nutrients necessary for cancer cell survival. However, the effectiveness of these therapies varies significantly among different cancer types and patients.This study addresses challenges such as the low proportion of tumor endothelial cells and the substantial heterogeneity across tissues and cancer types by collecting large-scale single-cell transcriptome sequencing data. For the first time at the pan-cancer level, it provides a detailed characterization of endothelial cell subtypes and their corresponding molecular phenotypes and functional states. Additionally, the study systematically elucidates the inherent transcriptomic features of endothelial cells from different cancer types and tissue origins. On this basis, it identifies common characteristics of tumor-associated endothelial cells that are consistent across different endothelial cell lineages, offering new insights for specifically targeting tumor endothelial cells.

　　The study identified two polarized subtypes of endothelial cells based on their tissue distribution and functional characteristics: CXCR4+ tip cells and SELE+ veins. These two cell populations exhibit distinct pro-angiogenic and pro-inflammatory states, respectively, and have unique spatial localization features. CXCR4+ tip cells tend to be enriched around tumor cells and are specifically abundant in tumor tissues, while SELE+ veins are associated with higher T cell infiltration but are relatively scarce in tumor tissues.

　　Importantly, the study observed that the ORR (objective response rate)of different cancer types to anti-angiogenic therapy in large-scale clinical trials correlated with the proportion of these cell types. Specifically, cancer types with a higher proportion of CXCR4+ tip cells showed a better response to anti-angiogenic therapy, whereas cancer types with relatively enriched SELE+ veins showed lower response levels. Conversely, in immunotherapy, cancers with a higher proportion of SELE+veins responded better, while those with enriched CXCR4+ tip cells tended to have lower response levels.

　　In summary, this study not only reveals the significant heterogeneity of tumor endothelial cells but also demonstrates how this heterogeneity affects cancer patients' responses to different therapies. This work provides a theoretical basis for the future development of precise anti-angiogenic therapies and offers data support for exploring related combination treatment strategies.

　　Ph.D. candidate Jinhu Li and Dr. Dongfang Wang are the co-first authors of the paper. Prof. Zemin Zhang and Dr. Dongfang Wang are the co-corresponding authors of the paper. The National Key Research and Development Program of China, the National Natural Science Foundation of China, and the Beijing Municipal Science and Technology Commission funded the project.

　　Link:https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwae231/7712496