Enhanced photodynamic therapy for overcoming tumor hypoxia: From microenvironment regulation to photosensitizer innovation

•Overview of enhanced photodynamic therapy against tumor hypoxia.•Reconstructing the tumor microenvironment by external and/or internal O2 to alleviate hypoxia.•Developing novel anti-hypoxia photosensitizers with anti-hypoxia mechanisms.•Combining photodynamic therapy with other treatment approaches to achieve complementary effects.•Evaluating the innovation of “theranostics” photosensitizers is the core impetus for the efficacy of PDT. Photodynamic therapy (PDT) has garnered an increasing interest by both researchers and clinicians as a non-invasive therapy that allows a selective treatment towards tumors temporally and spatially, which is a relatively safe strategy without obvious systemic side effects and drug resistance. However, the lack of O2 content in solid tumors is one of the most important factors limiting the effectiveness of PDT, as the hypoxic tumor regions not only induce tumor development and metastasis but also reduce the responsiveness of tumor tissues to PDT along with other treatments like chemotherapy and radiotherapy. Therefore, dealing with hypoxia is desirable and has become a hot research topic for both academic and clinical fields. This review summarizes the latest strategies and applications of reconstructing the tumor microenvironment and developing novel anti-hypoxia photosensitizers (PSs). It also summarizes the synergistic strategies that combine PDT with other treatment approaches to achieve complementary effects, significantly improving the treatment accuracy and efficacy. By evaluating several examples, this review concludes that the innovation of “theranostics” PS is the core impetus for the efficacy of PDT. In addition, it highlights that the structural designing of PS can effectively regulate the energy release process of the excited state and achieve imaging and PDT simultaneously.