Metabolic Reprogramming Shapes the Progression and Therapeutic Landscape of Ovarian Cancer.

Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to its asymptomatic progression, frequent late-stage diagnosis, and high rates of chemoresistance and recurrence. Beyond genetic alterations, recent studies highlight the central role of metabolic reprogramming in driving OC initiation, progression, and therapy resistance. OC cells exhibit dynamic metabolic reprogramming, enabling dynamic shifts between glycolysis and oxidative phosphorylation depending on environmental conditions and treatment pressures. In this review, we synthesize current understanding of key metabolic pathways altered in ovarian tumors, including enhanced aerobic glycolysis, glutamine addiction, dysregulated lipid metabolism, and mitochondrial adaptations. These metabolic shifts support rapid proliferation, redox homeostasis, immune evasion, and metastatic potential. We also explore how the metabolic landscape of OC is shaped by interactions with the tumor microenvironment, particularly through crosstalk with immune cells, cancer-associated fibroblasts, and adipocytes. Importantly, metabolic adaptations have been implicated in the emergence of cancer stem-like cells and in the development of resistance to platinum-based chemotherapy and PARP inhibitors. We also further discuss emerging therapeutic strategies targeting metabolic vulnerabilities, as well as combinatorial approaches integrating metabolic therapy with immunotherapy and DNA damage repair inhibition. Finally, we highlight how advances in metabolomics and spatial profiling are improving our ability to map metabolic heterogeneity and guide precision therapies in OC. This review underscores metabolic plasticity as a promising therapeutic vulnerability for overcoming drug resistance and improving outcomes in OC patients.