Strategic Design of Conquering Hypoxia in Tumor for Advanced Photodynamic Therapy

Photodynamic therapy (PDT), with its advantages of high targeting, minimally invasive, and low toxicity side effects, has been widely used in the clinical therapy of various tumors, especially superficial tumors. However, the tumor microenvironment (TME) presents hypoxia due to the low oxygen (O₂ ) supply caused by abnormal vascularization in neoplastic tissues and high O₂ consumption induced by the rapid proliferation of tumor cells. The efficacy of oxygen-consumping PDT can be hampered by a hypoxic TME. To address this problem, researchers have been developing advanced nanoplatforms and strategies to enhance the therapeutic effect of PDT in tumor treatment. This review summarizes recent advanced PDT therapeutic strategies to against the hypoxic TME, thus enhancing PDT efficacy, including increasing O₂ content in TME through delivering O₂ to the tumors and in situ generations of O₂ ; decreasing the O₂ consumption during PDT by design of type I photosensitizers. Moreover, recent synergistically combined therapy of PDT and other therapeutic methods such as chemotherapy, photothermal therapy, immunotherapy, and gas therapy is accounted for by addressing the challenging problems of mono PDT in hypoxic environments, including tumor resistance, proliferation, and metastasis. Finally, perspectives of the opportunities and challenges of PDT in future clinical research and translations are provided.