Hypoxia-induced cisplatin resistance in cancer: a comprehensive exploration of molecular mechanisms and novel therapeutic strategies

Tumor hypoxia is a critical contributor to cisplatin resistance, promoting molecular adaptations such as HIF-1α activation, reduced DNA repair capacity, metabolic reprogramming, and exosome-mediated drug efflux that collectively weaken cisplatin-induced cytotoxicity. This review integrates current evidence on these hypoxia-driven mechanisms and emphasizes how spatially heterogeneous hypoxic niches generate tumor subpopulations with distinct resistance profiles. Two therapeutic strategies show promising potential to counter this challenge: adjunct therapies that target hypoxia-related signaling and metabolic pathways, including HIF inhibitors, HDAC inhibitors, natural compounds, and metabolic modulators, and oxygenation approaches designed to reverse hypoxic stress. Notably, advances in nanotechnology-based oxygen-delivery systems provide sustained, localized reoxygenation of hypoxic regions, addressing limitations of conventional oxygen therapies. Although these interventions demonstrate strong preclinical efficacy, translation to consistent clinical benefit remains limited, partly due to inadequate hypoxia biomarkers and insufficient preclinical models that fail to replicate tumor oxygen gradients. Future progress will require biomarker-guided patient selection, optimized combination regimens, and early clinical evaluation of oxygen-delivery platforms to enhance cisplatin sensitivity and reduce hypoxia-driven chemoresistance.