Tumor hypoxia: Molecular pathways and therapeutic interventions

Tumor hypoxia not only promotes cancer progression, therapy resistance and immune escape, but it also creates therapeutically exploitable vulnerabilities. This review focuses on strategies that target hypoxic tumor adaptation, including hypoxia-activated prodrugs, direct and indirect hypoxia-inducible factor (HIF) inhibitors, and emerging non-HIF approaches targeting oxygen-sensing enzymes, chromatin modifiers, metabolic stress pathways and the unfolded protein response. We summarize representative agents, mechanisms of action, cancer contexts and clinical development status, with an emphasis on lessons from unsuccessful or context-dependent trials. Clinical translation remains challenged by hypoxia heterogeneity, inconsistent drug activation, limited pharmacodynamic validation and inadequate patient selection. Finally, we discuss how hypoxia biomarkers, functional imaging, spatial profiling and rational combinations might improve the precision deployment of hypoxia-targeted therapies.