Angiocrine factors in tumor microenvironment: bidirectional crosstalk, mechanistic insights, and therapeutic strategies.

Background

Tumor recurrence, metastasis, and treatment resistance represent core challenges in clinical oncology closely associated with the complex and dynamic tumor microenvironment (TME). Endothelial cells (ECs), key components of the TME, have functions that extend far beyond the traditional concept of tumor angiogenesis. In recent years, extensive research has revealed that ECs perform endocrine and paracrine functions by secreting angiocrine factors. These factors have been shown to contribute to tumor progression through multiple mechanisms, including remodeling of the tumor vascular niche, tumor immune suppression, metabolic reprogramming, and chemotherapy resistance. Therefore, a deeper understanding of the functional characteristics and regulatory mechanisms of angiocrine factors is crucial for identifying effective therapeutic targets in cancer. MAIN BODY This review integrates research advances on angiocrine factors associated with tumor progression, categorizing them into several key functional domains on the basis of their biological characteristics. We summarize the core signaling pathways regulated by angiocrine factors, including the Notch and Wnt pathways, and their crosstalk networks. We further elucidate the regulatory role of angiocrine factors in endothelial metabolism. Additionally, we explore the multifaceted functions of angiocrine factors in tumor dormancy, metastasis (tumor metastasis mediated by endothelial necroptosis), stemness maintenance, and immune suppression. Notably, this review highlights the complex crosstalk between ECs and tumor cells (TCs), as well as the roles of Notch and Wnt signaling pathways in vascular formation and endothelial metabolic. Finally, we discuss the current clinical limitations of anti-angiogenic therapies and combination treatment strategies, while highlighting the therapeutic potential and challenges of a "one-target, multiple-effects" approach.

Conclusion

Angiocrine factors are central regulatory mediators that coordinate tumor progression. The complexity and redundancy of the angiocrine factor networks is not only the root of limitations in anti-vascular therapies but also present opportunities for "one-target, multiple-effects" strategies. Rapid advances in single-cell transcriptomics, spatial transcriptomics, and lineage tracing technologies now provide powerful tools to decipher the spatiotemporal heterogeneity of vascular secretory factors and to track the clonal evolution and functional transitions of endothelial cells and their progenitor cells. These advances offer the potential to precisely identify key therapeutic targets, facilitating the development of novel anti-angiogenic strategies.