Reactive oxygen species (ROS)-mediated photodynamic therapy (PDT) is a promising cancer treatment that relies on the synergistic effects of light, photosensitizers (PSs), and oxygen. However, traditional PDT faces challenges such as limited light penetration depth, oxygen dependency, and light-induced heat generation. Recent advances in nanotechnology and nanomedicine have enabled the development of ROS-generating systems that overcome these limitations. This review summarizes current progress in ROS generation for cancer therapy and discusses innovative systems that expand PDT's scope. Key challenges include light penetration depth, PS localization, and oxygen dependency. Strategies to address these include upconversion systems, two-photon excitation, bioluminescence resonance energy transfer (BRET), X-ray excitation, and Cerenkov radiation. Additionally, oxygen self-supplement strategies, such as artificial red blood cells and perfluorocarbon nanoparticles, enhance PDT efficacy in hypoxic tumors. Catalase-based systems also show potential for improving oxygen availability. Overall, these innovations aim to enhance ROS generation and improve cancer treatment outcomes.Reactive oxygen species (ROS)-mediated photodynamic therapy (PDT) is a promising cancer treatment that relies on the synergistic effects of light, photosensitizers (PSs), and oxygen. However, traditional PDT faces challenges such as limited light penetration depth, oxygen dependency, and light-induced heat generation. Recent advances in nanotechnology and nanomedicine have enabled the development of ROS-generating systems that overcome these limitations. This review summarizes current progress in ROS generation for cancer therapy and discusses innovative systems that expand PDT's scope. Key challenges include light penetration depth, PS localization, and oxygen dependency. Strategies to address these include upconversion systems, two-photon excitation, bioluminescence resonance energy transfer (BRET), X-ray excitation, and Cerenkov radiation. Additionally, oxygen self-supplement strategies, such as artificial red blood cells and perfluorocarbon nanoparticles, enhance PDT efficacy in hypoxic tumors. Catalase-based systems also show potential for improving oxygen availability. Overall, these innovations aim to enhance ROS generation and improve cancer treatment outcomes.