Application of Hypoxia-Activated Prodrugs in Tumor Therapy: Design Strategies and Perspectives

Hypoxia is one of the common characteristics of solid tumors, primarily resulting from an imbalance between rapid tumor proliferation and disordered angiogenesis. Hypoxic heterogeneity promotes tumor invasion and metastasis, metabolic reprogramming, immune suppression, and angiogenesis. Moreover, tumor hypoxia is one of the major drivers of widespread drug resistance observed in cancer therapy. Hypoxia also presents opportunities for targeted tumor therapy with hypoxia-targeted prodrugs (HAPs) showing great potential in cancer treatment. This perspective summarizes the fundamental principles, major classifications, and drug design strategies of HAPs, as well as highlights the innovative integration of HAPs with other therapeutic modalities. This article endeavors to provide a comprehensive perspective on the evolving field of hypoxia-targeting agents, offering valuable insights into future drug development.