Evaluating pheophorbide-a as a photosensitizer in oral cancer photodynamic therapy: A systematic review

Oral squamous cell carcinoma (OSCC) is commonly treated with surgery, radiotherapy and chemotherapy, which often cause significant morbidity. Photodynamic therapy (PDT) has emerged as a minimally invasive alternative. Pheophorbide-a (Pa), a second-generation photosensitizer, shows promise, but has not been critically reviewed in oral malignancies. The aim of the present systematic review was to evaluate preclinical evidence on the mechanisms of action, efficacy and safety of Pa-mediated PDT (Pa-PDT) in oral oncology.A systematic search of PubMed, Embase, Scopus, and Cochrane Library was conducted in line with the PRISMA 2020 guidelines (PROSPERO ID: CRD420251066127). Eligible studies included in vitro or in vivo models using Pa-PDT in oral malignancies. Data on therapeutic outcomes, the mechanisms of action, and study quality was extracted and analyzed. Nine studies were included. Pheophorbide-a-induced photodynamic therapy consistently induced apoptosis, autophagy and endoplasmic reticulum (ER) stress through reactive oxygen species (ROS) and mitochondrial dysfunction. It also overcame multidrug resistance by downregulating HOXC6 and MDR1. Conjugation with targeting peptides, nanocarriers and immune checkpoint inhibitors enhanced selectivity and cytotoxicity.Pheophorbide-a demonstrated favorable photophysical properties, including strong red-light absorption (664-675nm), high singlet oxygen yield and minimal dark toxicity. Evidence was limited by small sample sizes, heterogeneous protocols and the absence of human trials. Pheophorbide-a-induced photodynamic therapy shows antitumor activity in preclinical OSCC models, supporting further preclinical development and carefully designed early-phase trials. Translation should proceed only within early-phase trials that directly benchmark Pa against the approved photosensitizers, using standardized protocols.