HIF-1α-mediated metabolic reprogramming in hypoxia-driven tumor metastasis

Tumor metastasis is a multistep process that requires profound metabolic plasticity to support cancer cell invasion, survival in circulation, colonization of distant organs, and metastatic outgrowth. Hypoxia is a hallmark of solid tumors and a major driver of metastatic progression. As a central transcriptional regulator of the hypoxic response, hypoxia-inducible factor-1α is stabilized under oxygen deprivation and orchestrates broad metabolic reprogramming by regulating glycolysis, lactate production and export, mitochondrial respiration, lipid metabolism, amino acid utilization, redox homeostasis, and interactions with the tumor microenvironment. These metabolic adaptations not only provide bioenergetic and biosynthetic support for disseminating cancer cells but also promote epithelial-mesenchymal transition, extracellular matrix remodeling, angiogenesis, immune evasion, and premetastatic niche formation. In this review, we summarize current knowledge regarding the mechanisms by which hypoxia-inducible factor-1α-mediated metabolic reprogramming contributes to different stages of the metastatic cascade. We also discuss the therapeutic potential and limitations of targeting hypoxia-inducible factor-1α-associated metabolic vulnerabilities in metastatic cancer. A better understanding of the context-dependent functions of hypoxia-inducible factor-1α may facilitate the development of more effective anti-metastatic strategies.