The article reviews the current status and potential opportunities of reactive oxygen species (ROS) generation for cancer therapy, focusing on photodynamic therapy (PDT) and non-photodynamic procedures. ROS, primarily generated by photosensitizers (PSs) under light activation, play a crucial role in PDT's efficacy. However, traditional PDT faces several challenges, including limited light penetration depth, oxygen dependency, light-induced heat generation, and the need for specific PS localization. Recent advances in nanotechnology have led to the development of innovative systems that enhance ROS generation and overcome these limitations. Key strategies include: 1. **Depth Penetration**: Techniques such as upconversion nanoparticles (UCNPs), two-photon excitation, self-illumination through bioluminescence resonance energy transfer (BRET), X-ray excitation, and Cerenkov radiation are explored to improve light penetration and activation of PSs in deep tissues. 2. **Oxygen Self-Supplement**: Artificial red blood cells (ARCs) and perfluorocarbon nanoparticles (PFCs) are used to enhance oxygen availability during PDT, particularly in hypoxic tumors. 3. **Diverse Stimulations**: Systems that use heat, pH changes, or other stimuli to trigger ROS production are discussed, aiming to reduce the reliance on light activation and minimize side effects. The review highlights the potential of these advanced strategies to expand the scope of PDT and improve its clinical application in cancer therapy.The article reviews the current status and potential opportunities of reactive oxygen species (ROS) generation for cancer therapy, focusing on photodynamic therapy (PDT) and non-photodynamic procedures. ROS, primarily generated by photosensitizers (PSs) under light activation, play a crucial role in PDT's efficacy. However, traditional PDT faces several challenges, including limited light penetration depth, oxygen dependency, light-induced heat generation, and the need for specific PS localization. Recent advances in nanotechnology have led to the development of innovative systems that enhance ROS generation and overcome these limitations. Key strategies include: 1. **Depth Penetration**: Techniques such as upconversion nanoparticles (UCNPs), two-photon excitation, self-illumination through bioluminescence resonance energy transfer (BRET), X-ray excitation, and Cerenkov radiation are explored to improve light penetration and activation of PSs in deep tissues. 2. **Oxygen Self-Supplement**: Artificial red blood cells (ARCs) and perfluorocarbon nanoparticles (PFCs) are used to enhance oxygen availability during PDT, particularly in hypoxic tumors. 3. **Diverse Stimulations**: Systems that use heat, pH changes, or other stimuli to trigger ROS production are discussed, aiming to reduce the reliance on light activation and minimize side effects. The review highlights the potential of these advanced strategies to expand the scope of PDT and improve its clinical application in cancer therapy.