Metabolic reprogramming and molecular crosstalk at the cancer–endothelial interface in ovarian carcinoma

Ovarian carcinoma (OC) is the most lethal gynecological malignancy, with high mortality due to late-stage diagnosis and the development of chemoresistance. Tumor progression relies on a complex interplay between cancer cells and the tumor microenvironment (TME), particularly endothelial cells (ECs), which support angiogenesis, nutrient supply, and metastasis. Aberrant neovascularization, driven primarily by VEGF signaling and hypoxia-inducible factors (HIFs), establishes a structurally and functionally abnormal vasculature that enhances tumor growth and dissemination. In the TME, ECs and OC cells undergo metabolic reprogramming, with glycolysis, fatty acid oxidation (FAO), and amino acid metabolism supporting angiogenesis, proliferation, redox balance, and chemoresistance. The bidirectional nutrient exchange establishes a metabolic symbiosis sustaining angiogenesis stimulation, tumor growth and survival under hypoxia and a pro-oxidative TME. Ultrastructural adaptations, including tunneling nanotubes (TNTs), facilitate direct cytoplasmic and organelle exchange, enhancing mitochondrial transfer, metabolic support, and therapy resistance. The formation of EC TNTs is regulated by stress-responsive pathways, including HIF-1α, VEGF, and Nrf2, which integrate hypoxia, oxidative stress, and metabolic signaling to reinforce vascular remodeling. This intricate network of signaling and metabolic interactions establishes a self-sustaining vascular niche that drives tumor aggressiveness and limits therapeutic efficacy. Understanding these mechanisms provides insight into potential therapeutic interventions, aiming to disrupt the cooperative tumor-EC network and overcome chemoresistance in OC.