Hypoxia-activated prodrugs in cancer therapy: Medicinal chemistry, mechanisms, and precision therapeutic strategies

Hypoxia is a hallmark of solid tumors and is expressed by low oxygen levels. It drives cancer progression, metastasis, and resistance to radiotherapy, chemotherapy, and immunotherapy. It activates the hypoxia-inducible factor (HIF) pathway and adaptive responses, including the unfolded protein response and nuclear factor kappa B signaling. Hypoxia-activated prodrugs (HAPs) initiate their action in low-oxygen microenvironments, liberating cytotoxic agents such as DNA-damaging radicals or kinase inhibitors while remaining inert in normoxic healthy tissue. This review surveys medicinal chemistry strategies underlying oxygen-responsive hypoxia-activated prodrugs (HAPs), including nitroaromatic agents (e.g., evofosfamide/TH-302), N-oxide derivatives (e.g., tirapazamine and AQ4N), quinone methide–based systems, metal-coordinated complexes (e.g., Pt(IV) and Co(III)), and azo-bond–containing compounds, with emphasis on their bioreductive activation pathways and self-immolative drug-release mechanisms. Preclinical studies have validated the ability of HAPs to selectively eradicate hypoxic tumor cells, overcome resistance to radiotherapy, and improve chemotherapy and immunotherapy outcomes. Despite significant results, clinical translation faces obstacles, including tumor heterogeneity, poor drug penetration into necrotic cores, and a lack of patient stratification biomarkers, such as pimonidazole imaging or gene profiling. Future directions focus on personalized medicine via hypoxia biomarkers and nanotechnology for enhanced delivery. Other developments include rational combinations with photodynamic therapy and anti-programmed cell death protein-1 agents to augment therapeutic indices. Thus, HAPs hold substantial promise for precision oncology, improving treatment specificity, reducing resistance, and optimizing patient outcomes in hypoxia-driven cancers.