Photodynamic therapy: research progress and paradigm evolution from mechanism innovation to clinical breakthrough in...

FactsPhotodynamic therapy (PDT) is a minimally invasive anticancer modality based on the light-mediated activation of photosensitizers to generate reactive oxygen species and induce tumor cell death.PDT has demonstrated clinical efficacy in treating various tumor types, including esophageal cancer, gastric cancer, lung cancer, skin cancer, bladder cancer, cervical cancer, ovarian cancer, and glioblastoma.The antitumor effects of PDT are mediated not only by direct tumor cell killing but also by vascular damage, immunogenic cell death, and activation of antitumor immune responses.Nanotechnology-based photosensitizer delivery systems and tumor microenvironment modulation strategies have improved the targeting, oxygenation, and therapeutic efficacy of PDT.Combination strategies that integrate PDT with chemotherapy, radiotherapy, targeted therapy, and immunotherapy are an important way to enhance clinical efficacy and overcome treatment resistance.Open QuestionsHow can photosensitizer selectivity, tumor accumulation, and tissue penetration be further improved to enhance PDT efficacy while minimizing off-target toxicity?What are the optimal light parameters, drug-light intervals, and dosimetry standards for different tumor types and treatment settings?How can tumor hypoxia and oxygen depletion during PDT be effectively overcome in deep-seated or poorly vascularized tumors?What is the optimal timing and sequencing of PDT combined with immunotherapy, chemotherapy, or radiotherapy to maximize the antitumor effect?How can large-scale, multicenter clinical trials be designed to standardize PDT protocols and validate their long-term efficacy, safety, and clinical applications? Photodynamic therapy is a noninvasive anticancer treatment that uses light-activated photosensitizers to generate reactive oxygen species. However, its clinical efficacy is severely limited by tumor hypoxia and rapid oxygen depletion during the type II photochemical reaction. To address these challenges, we synthesized data from randomized controlled trials and meta-analyses published between 2000 and 2025. Our review shows that photodynamic therapy significantly increases survival rates in patients with malignant pleural effusion and achieves high complete response rates in patients with esophageal and gastric cancers. However, a risk-of-bias assessment reveals limitations in study design regarding blinding and sample size. Crucially, we identify gas-mediated therapies as the next paradigm shift. This review discusses emerging strategies to overcome tumor hypoxia and improve the efficacy of photodynamic therapy. These strategies include oxygen-generating nanoplatforms, tumor microenvironment modulation, and combination approaches with chemotherapy, radiotherapy, and immunotherapy. Additionally, we discuss the critical role of sequential immunotherapy and propose standardized dosimetry protocols that report irradiance and drug-light intervals. These protocols aim to facilitate global regulatory harmonization and clinical reproducibility.