Combating the hypoxia limit of photodynamic therapy through reversing the survival-related pathways of cancer cells

• The hypoxia limit of PDT and the common solutions were elaborated. • Survival-related pathways triggered by hypoxia after PDT treatment was introduced. • Typical strategies of reversing survival pathways for enhanced PDT were discussed. Photodynamic therapy (PDT) is extensively used in the treatment of varied diseases due to its noninvasive characteristic. However, resistance will also be developed due to tumor hypoxia, which hinders the therapeutic developments. To increase the generation of intracellular reactive oxygen species (ROS), oxygen‐carrying and producing strategies were adopted, but with limited efficacy. At the cellular level, a series of survival pathways are activated to alleviate the ROS-mediated damage caused by PDT, resulting in tumor regrowth and PDT failure. Therefore, perturbating or reversing these survival pathways provides another avenue for boosting the PDT efficacy. In this review, we summarized the progress about combating the hypoxia limit of PDT through reversing the cell survival-related pathways. The hypoxia-induced survival pathways in cancer cells were firstly outlined. Upon reversing the survival-related pathways, including mitochondrial electron transport chain, HIF-1 induced survival pathway, and anti-apoptosis pathway, the PDT resistance could be greatly alleviated, which demonstrates the promising future of these advanced strategies. Overall, although PDT is oxygen-dependent and cancer cells are normally hypoxic, great efforts have been made to combat hypoxia and improve the clinical efficacy of PDT.