Understanding tumour endothelial cell heterogeneity and function from single-cell omics

Anti-angiogenic therapies (AATs) are used to treat different types of cancers. However, their success is limited owing to insufficient efficacy and resistance. Recently, single-cell omics studies of tumour endothelial cells (TECs) have provided new mechanistic insight. Here, we overview the heterogeneity of human TECs of all tumour types studied to date, at the single-cell level. Notably, most human tumour types contain varying numbers but only a small population of angiogenic TECs, the presumed targets of AATs, possibly contributing to the limited efficacy of and resistance to AATs. In general, TECs are heterogeneous within and across all tumour types, but comparing TEC phenotypes across tumours is currently challenging, owing to the lack of a uniform nomenclature for endothelial cells and consistent single-cell analysis protocols, urgently raising the need for a more consistent approach. Nonetheless, across most tumour types, universal TEC markers (ACKR1, PLVAP and IGFBP3) can be identified. Besides angiogenesis, biological processes such as immunomodulation and extracellular matrix organization are among the most commonly predicted enriched signatures of TECs across different tumour types. Although angiogenesis and extracellular matrix targets have been considered for AAT (without the hoped success), the immunomodulatory properties of TECs have not been fully considered as a novel anticancer therapeutic approach. Therefore, we also discuss progress, limitations, solutions and novel targets for AAT development.