From Low to No O₂-Dependent Hypoxia Photodynamic Therapy (hPDT): A New Perspective

The advent of photochemical techniques has revolutionized the landscape of biology and medical sciences. Especially appealing in this context is photodynamic therapy (PDT), which is a photon-initiated treatment modality that uses cytotoxic reactive oxygen species (ROS) to kill malignant cells. In the past decade, PDT has risen to the forefront of cancer therapy. Its optical control enables noninvasive and spatiotemporal manipulation of the treatment process, and its photoactive nature allows unique patterns to avoid drug resistance to conventional chemotherapeutics. However, despite the impressive advances in this field, achieving widespread clinical adoption of PDT remains difficult. A major concern is that in the hostile tumor microenvironment, tumor cells are hypoxic, which hinders ROS generation during PDT action. To overcome this "Achilles' heel", current strategies focus primarily on the improvement of the intratumoral O₂ perfusion, while clinical trials suggest that O₂ enrichment may promote cancer cell proliferation and metastasis, thereby making FDA approval and clinical transformation of these paradigms challenging.In an effort to improve hypoxia photodynamic therapy (hPDT) in the clinic, we have explored "low to no O₂-dependent" photochemical approaches over the years to combat hypoxia-induced resistance. In this Account, we present our contributions to this theme during the past 5 years, beginning with low O₂-dependent approaches (e.g., type I superoxide radical (O₂^•-) generator, photodynamic O₂-economizer, mitochondrial respiration inhibition, cellular self-protective pathway modulation, etc.) and progressing to O₂-independent strategies (e.g., autoadaptive PDT/PTT complementary therapy, O₂-independent artificial photoredox catalysis in cells). These studies have attracted tremendous attention. Particularly in the pioneering work of 2018, we presented the first demonstration that the O₂^•--mediated partial O₂-recyclability mechanism can overcome PDT resistance ( J. Am. Chem. Soc. 2018, 140, 14851-14859). This launched an era of renewed interest in type I PDT, resulting in a plethora of new O₂^•- photogenerators developed by many groups around the world. Moreover, with the discovery of O₂-independent photoredox reactions in living cells, artificial photoredox catalysis has emerged as a new field connecting photochemistry and biomedicine, stimulating the development of next-generation phototherapeutic tools ( J. Am. Chem. Soc. 2022, 144, 163-173). Our recent work also disclosed that "photoredox catalysis in cells" might be a general mechanism of action of PDT ( Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2210504119). These emergent concepts, molecular designs, photochemical mechanisms, and applications in cancer diagnosis and therapeutics, as well as pros and cons, are discussed in depth in this Account. It is expected that our contributions to date will be of general use to researchers and inspire future efforts to identify more promising hPDT approaches that better meet the clinical needs of cancer therapy.