Abstract
BACKGROUND: Photodynamic therapy (PDT) is a noninvasive cancer treatment that works by using light to stimulate the production of excessive cytotoxic reactive oxygen species (ROS), which effectively eliminates tumor cells. However, the therapeutic effects of PDT are often limited by tumor hypoxia, which prevents effective tumor cell elimination. The oxygen (O(2)) consumption during PDT can further exacerbate hypoxia, leading to post-treatment adverse events. OBJECTIVES: This review aims to explore the potential of cuproptosis, a recently discovered copper-dependent form of programmed cell death, to enhance the anticancer effects of PDT. Cuproptosis is highly dependent on mitochondrial respiration, specifically the tricarboxylic acid (TCA) cycle, and can increase O(2) and ROS levels or decrease glutathione (GSH) levels, thereby improving PDT outcomes. METHODS: The review discusses the latest research advancements in the field, detailing the mechanisms that regulate cuproptosis and PDT. It also explores how nanoparticle (NP)-based strategies can be used to exploit the synergistic potential between cuproptosis and PDT. The article examines the prospects of synergistic anticancer activity guided by nanodelivery systems, which could overcome the challenges associated with hypoxia in cancer treatment. CONCLUSIONS: The combination of cuproptosis and PDT, facilitated by NP-based delivery systems, presents a promising approach to enhance the effectiveness of cancer therapy. The review concludes by discussing the challenges and future research directions for this combination therapy, highlighting the need for further investigation into the mechanisms and optimization of treatment strategies to improve outcomes in cancer treatment.