Rewiring Tumor Lifelines: Translating Hypoxia- and Pseudohypoxia-Driven Angiogenesis into Therapeutic Breakthroughs

Hypoxia and the evolving concept of pseudohypoxia are critical in driving tumor angiogenesis, contributing to malignancy progression and therapeutic resistance. Angiogenesis, a common feature of many solid tumors, is promoted by hypoxia-induced overexpression of pro-angiogenic factors (e.g., VEGF, FGF) and genetic mutations (e.g., VHL, SDH) that stabilize hypoxia-inducible factors (HIF) even in normal oxygen conditions, a phenomenon known as pseudohypoxia. Recent experimental studies challenge the view that hypoxia universally enhances vessel growth. In certain models, severe oxygen deprivation impairs angiogenesis. Furthermore, tumor-mediated metabolic reprogramming can drive immune evasion via HIF stabilization in immune cells. These paradoxes, together with persistent therapy resistance and the limited effectiveness of current anti-angiogenic treatments, reveal critical gaps in our understanding of how hypoxic signaling modulates vascular and immune dynamics within the tumor microenvironment. These complexities demand more detailed exploration of underlying processes and the development of innovative therapeutic strategies. Here, we review recent mechanistic studies on tumor angiogenesis, summarizing therapeutic and diagnostic advances from both preclinical and clinical studies. We further discuss strategies to exploit hypoxic vulnerabilities, including HIF inhibitors, hypoxia-activated prodrugs, vascular normalization, combination regimens to restore immunity, biomarker-guided patient selection, and advanced hypoxia-targeted imaging to improve outcomes in angiogenesis-driven cancers.